@article {pmid41284069,
year = {2025},
author = {Rodrigues, KDC and Oliveira, MDC and de Souza, IC and Igansi, AW and Lopes, AVB and de Oliveira Pacheco, C and Hass, SE and Schumacher, RF and Luchese, C},
title = {Sex-dependent therapeutic effects of nano-curcumin on alzheimer's disease: enhanced cognitive and physiological restoration in female mice.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41284069},
issn = {1432-2072},
support = {PqG 24/2551-0001249-4//Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul/ ; 160674/2020-4//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
abstract = {Curcumin (Cur) is a bioactive compound with neuroprotective and anti-inflammatory effects, though its clinical application is limited by poor bioavailability. This study assessed the impact of nanocapsulated curcumin (NcCur), formulated Eudragit (EUD) polymer, in a sporadic Alzheimer's disease (AD) mouse model induced by intracerebroventricular streptozotocin (STZ), with attention to sex-specific differences. Mice received STZ (3 nmol/3 µL) or 0.9% saline on days 1 and 3, followed by intragastric treatment with Cur or NcCur (10 mg/kg, on alternate days) from day 22 until euthanasia - a dose previously shown to be effective in behavioral and biochemical modulation in rodent models of neurodegeneration. Behavioral assessments included open field, elevated plus maze (EPM), tail suspension (TST), object recognition, Y-maze, and step-down avoidance tasks (SDAT), performed before and after treatment. After euthanasia, thymus, spleen and adrenal glands were weighed; biochemical assays evaluated oxidative stress, monoaminergic and cholinergic enzymes, and Na[+]K[+]-ATPase activity. NcCur improved short- and long-term memory in both sexes, with greater effects in females (42% and 35%) than males (28% and 25%). In the EPM, NcCur increased open arm time more prominently in females (40%) than males (25%), while TST immobility time was reduced similarly in both. Spatial and aversive memory improved in both sexes, but females showed greater performance in the SDAT. Biochemical analyses showed reductions in reactive species in males (45%) and females (55%) with NcCur; Na[+]K[+]-ATPase activity increased in females (60%) and males (50%). AChE activity was restored in both sexes. NcCur reduced MAO-A/B activities more in females (65%/55%) than in males (45%/35%). Thymus and spleen weights were normalized in both sexes, with stronger effects in females. NcCur also mitigated alterations in thymus and spleen relative weights, suggesting immunomodulatory effects. Some biochemical and behavioral responses were more prominent in females, both sexes benefited from treatments. These findings suggest that NcCur enhances Cur therapeutic potential through multimodal actions linked involving modulation of oxidative stress, cholinergic and monoaminergic systems, and immune-related parameters. NcCur emerges as a promising candidate for AD-like intervention in both sexes.},
}

@article {pmid41282905,
year = {2025},
author = {Andrews, D and Golchi, S and Collins, DL and , },
title = {A digital twin methodology using real patient data for sample size reduction in Alzheimer's disease randomized controlled clinical trials.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.28.25338899},
pmid = {41282905},
abstract = {INTRODUCTION: Recruitment for Alzheimer's disease randomized controlled trials (RCTs) is difficult and expensive. To reduce RCT sample sizes, our Digital Twin Trial (DTT) methodology combines an interpretable cognitive decline prediction model with prediction-powered inference.

METHODS: For DTT participants, our model identifies similar individuals ("Digital Twins") from a retrospective database and uses their cognitive scores to predict decline. Predictions adjust observed scores, reducing variance within treatment groups. We simulated 18-month DTTs and standard RCTs using mixed effects models of decline in Alzheimer's Disease Neuroimaging Initiative subjects meeting lecanemab's Phase 3 inclusion criteria.

RESULTS: Predicted and observed change in Clinical Dementia Rating Sum-of-Boxes correlated at r = 0.4. DTTs required 1,855 subjects versus 2,170 for standard RCTs to detect a simulated 25% decline-slowing drug effect at 0.9 power. DTT Type 1 error was consistent with 0.05.

DISCUSSION: DTTs could reduce recruitment and cost burdens. Model interpretability could help clinicians trust individualized prognoses.},
}

@article {pmid41282780,
year = {2025},
author = {Yang, B and Earnest, T and Bilgel, M and Albert, MS and Johnson, SC and Davatzikos, C and Erus, G and Masters, CL and Resnick, SM and Miller, MI and Bakker, A and Morris, JC and Benzinger, TLS and Gordon, BA and Sotiras, A and , and , },
title = {Predicting future cognitive impairment in preclinical Alzheimer's disease using multimodal imaging: a multisite machine learning study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.15.25337507},
pmid = {41282780},
abstract = {UNLABELLED: Predicting the likelihood of developing Alzheimer's disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([ [18] F]-florbetapir and [ [11] C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials.

HIGHLIGHTS: Machine learning can predict future cognitive impairment in preclinical Alzheimer'sModels achieved high out-of-sample ROC-AUC on external sites and PET tracersModels were able to distinguish cognitively stable from decliners in the A4 cohortML cohort enrichment enhanced secondary treatment effect detection in the A4 cohort.},
}

@article {pmid41282773,
year = {2025},
author = {Ackley, SF and La Joie, R and Caunca, M and Mukherjee, S and Choi, SE and Trittschuh, EH and Crane, PK and Hayes-Larson, E and , },
title = {Substituting Blood-Based Biomarkers for Imaging Measures in Alzheimer's Disease Studies: Implications for Sample Size and Bias.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.06.25339696},
pmid = {41282773},
abstract = {BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) pathology are appealing options in large population-based studies due to their low cost, minimal invasiveness, and feasibility of collection in non-clinical settings. Despite these benefits, blood-based biomarkers have lower test-retest reliability than neuroimaging measures like amyloid positron emission tomography (amyloid-PET) Centiloids; trade-offs in power and bias remain unexplored.

METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau181 or p-tau217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.

RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 3 to 6 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.

CONCLUSIONS: Due to their lower cost and ease of collection compared with neuroimaging, blood-based biomarkers facilitate AD pathology measures on larger, more diverse samples with longitudinal follow-up. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.},
}

@article {pmid41282720,
year = {2025},
author = {Khorsand, B and Teichrow, D and Ghanbarian, E and Zheng, L and Sajjadi, SA and Glover, CM and Grill, JD and Rabin, LA and Ezzati, A},
title = {Scalable Markers for Early Cognitive Decline: Plasma p-tau217, Subjective Cognitive Concerns, and Digital Testing: Results from the A4/LEARN studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.14.25338009},
pmid = {41282720},
abstract = {BACKGROUND AND OBJECTIVES: Although amyloid positron emission tomography (PET) and Cerebrospinal fluid (CSF) biomarkers remain the standard for confirming Alzheimer's disease (AD) pathology, their use is impractical for screening or routine prognostic assessment. Plasma phosphorylated tau 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We tested whether these measures independently predict the onset of cognitive impairment and whether combining them improves prognostic accuracy.

METHODS: We analyzed 1,071 cognitively unimpaired adults aged 65-85 years from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial (amyloid-positive; solanezumab or placebo arms) and the parallel Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort (amyloid-negative). At baseline, participants completed plasma p-tau217 measurement, the Cognitive Function Index (CFI), and the Cogstate Computerized Battery (CCB). Over 240 weeks of follow-up, incident impairment was defined as conversion from a Global Clinical Dementia Rating Score (CDR-GS) of 0 to 0.5 or higher. The predictive value of each measure for subsequent decline was examined after adjustment for demographic and genetic covariates.

RESULTS: During the follow-up, 365 of 1,071 participants (34.1%) developed cognitive impairment. Higher plasma p-tau217 (per-standard-deviation increase) was associated with higher odds of converting to CDR-GS>0 across all cohorts: A4-Placebo (HR=1.56; 95% CI, 1.37-1.78), A4-Solanezumab (HR=1.46; 95% CI, 1.29-1.65), LEARN (HR=1.25; 95% CI, 1.05-1.48). Similarly, higher CFI predicted incident impairment: A4-Placebo (HR=1.59; 95% CI, 1.42-1.79), A4-Solanezumab (HR=1.67; 95% CI, 1.47-1.91), LEARN (HR=1.37; 95% CI, 1.12-1.68). Lower CCB also conferred higher risk: A4-Placebo (HR=0.76; 95% CI, 0.65-0.91), A4-Solanezumab (HR=0.73; 95% CI, 0.62-0.87), LEARN (HR=0.68; 95% CI, 0.53-0.87). In models including all three predictors, each remained independently associated with progression.

CONCLUSION: Plasma p-tau217, subjective cognitive concerns, and computerized cognitive testing each independently predicted progression to cognitive impairment in cognitively unimpaired older adults. Together, these non-invasive and scalable measures provide practical tools for risk stratification years before clinical diagnosis. Combining biological, subjective, and digital markers may support earlier detection in clinical care and enhance efficiency in prevention trial enrollment.},
}

@article {pmid41282187,
year = {2025},
author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Dore, V and Laws, SM},
title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7911284/v1},
pmid = {41282187},
issn = {2693-5015},
abstract = {Accumulation of brain amyloid beta (Aβ) is a key pathological hallmark of Alzheimer's disease (AD) and begins many years before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which this accumulation exceeds a critical threshold, may enable early intervention and treatment to slow or prevent the onset of AD. We utilised published genome-wide association studies (GWAS) to develop polygenic scores (PGS) based on AD risk (PGS risk) and resilience (PGS resilience). We tested whether these could predict (i) whether an individual was an accumulator of Aβ ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ is estimated to exceed a threshold of 20 centiloids (CL)('Estimated Age at onset of Aβ'; AAO-Aβ) among 2175 participants (1158 with AAO Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. Additionally, we conducted genome-wide association studies (GWAS) of these traits and developed phenotype-specific PGSs using cross-validation (CV). Higher PGS risk was associated with a greater risk of being an accumulator and a younger AAO-Aβ. When stratified by number of APOE ε4 alleles, PGS risk predicted Accumulator Status in APOE ε4 heterozygotes, and AAO-Aβ in ε4 non-carriers and heterozygotes, with the same directions of effect as were seen in the whole cohort. PGS resilience was not significantly associated with Accumulator Status, but higher PGS resilience was associated with later AAO-Aβ overall and in ε4 heterozygotes. Trait-specific PGSs, developed using CV, were not significantly associated with either trait overall and the direction of association varied across CV folds. Polygenic scores, alongside other risk factors, may be useful for identifying individuals at risk of accumulating Aβ, and predicting the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.},
}

@article {pmid41282120,
year = {2025},
author = {Li, M and Niu, S and Xu, Y and Li, J and Hu, X and Liu, D and Atik, M and Xu, X and Wang, L and Taner, NE and Tao, C},
title = {Bridging the Computational-Experimental Gap: Leveraging Large Language Model to Prioritize Alzheimer's Therapeutics Based on Comparison of Learning Models.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7811754/v1},
pmid = {41282120},
issn = {2693-5015},
abstract = {Alzheimer's Disease (AD) [1] is a progressive neurodegenerative disorder with limited therapeutic options, driving interest in drug repurposing to accelerate treatment discovery. Drug repurposing has emerged as a promising strategy to accelerate therapeutic discovery by repositioning existing drugs for new clinical indications. Recent computational repurposing approaches, including knowledge graph reasoning, transcriptomic signature analysis, and integrative literature mining, have demonstrated strong predictive capabilities [2] . However, these methods often yield divergent drug rankings, which makes it difficult to decide which candidates to advance for experimental follow-up and results in substantial gaps between computational predictions and feasible in vivo validation [2] .To bridge this computational-experimental gap, we proposed an advanced prioritization framework leveraging large language models (LLMs). Our method systematically evaluated three state-of-the-art (SOTA) and representative computational methods (TxGNN [3] , Composition-based Graph Convolutional Network (CompGCN) [4] , and a regularized logistic regression (RLR) [5] , to analyze both their predictive performance and pharmaceutical class distributions. By integrating the strengths and divergences of these models, we generated a unified, streamlined list of 90 candidate drugs for further prioritization. We then utilized an LLM-based agent to perform evidence synthesis from biomedical literature abstracts for each candidate. This process mimics expert manual curation but significantly reduces human effort and time by efficiently distilling vast textual data into actionable insights. Applying consistent and transparent selection criteria, we obtained a refined and prioritized list of drug candidates suitable for subsequent in vivo experimental validation. The robustness and clinical relevance of our framework were validated using real-world data from Alzheimer's patient cohorts, clinical trial registries, and expert pharmacological reviews. This comprehensive validation confirmed that our LLM-driven approach enhances efficiency, consistency, scalability, and generalizability. By integrating computational predictions with scalable evidence synthesis and multifaceted validation, our framework facilitated rapid and informed prioritization of repurposed drugs. Our framework can potentially accelerate the translational pathway toward viable AD therapeutics. Moreover, the versatility of our framework can also be applied to drug repurposing efforts for other diseases beyond AD.},
}

@article {pmid41281734,
year = {2025},
author = {Wang, D and Florian, H and Lynch, SY and Robieson, W and Zhuang, R and Kusiak, C and Ross, JL and Walsh, JR and Graff, O},
title = {Using AI-generated digital twins to boost clinical trial efficiency in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70181},
pmid = {41281734},
issn = {2352-8737},
abstract = {INTRODUCTION: Machine learning models leverage baseline data to create artificial intelligence (AI)-generated digital twins (DTs)-individualized predictions of each participant's clinical outcomes if they had received placebo. Incorporating DTs may increase statistical power or reduce required sample sizes in Phase 2 or 3 trials, and therefore improve efficiency in Alzheimer's disease (AD) trials. Here we demonstrate these properties using data from an AD Phase 2 clinical trial (AWARE, NCT02880956).

METHODS: A conditional restricted Boltzmann machine (CRBM) model was trained on historical clinical trials and observational data from 6736 unique subjects after data harmonization to generate DTs of participants from the AWARE trial. The AWARE trial enrolled 453 subjects with mild cognitive impairment (MCI) or mild AD. DTs were assessed as prognostic covariates to evaluate gains in variance and sample size reduction.

RESULTS: Positive partial correlation coefficients were found between DTs and change score from baseline in key cognitive assessments ranging from 0.30 to 0.39 at Week 96 in the AWARE trial. These correlations were consistent with validation results from three independent trials, which ranged from 0.30 to 0.46. Total residual variance was reduced by ~9% to 15% with DTs. While maintaining statistical power, DTs could reduce total sample size by ~9% to 15%, and control arm sample size by 17% to 26% in future AD trials.

DISCUSSION: Efficiency was improved in AD clinical trials using machine learning models to generate prognostic DTs by including them in statistical analysis modeling. This methodology aligns with regulatory guidance and represents an application of machine learning models suitable for the analysis of pivotal trial data. Validated DTs have the potential to improve clinical development efficiency in AD and in other neurological indications.

HIGHLIGHTS: Digital twins (DTs) were generated by artificial intelligence (AI) models trained on historical datasets.Use of digital twin (DT) as a covariate in the analysis model can reduce treatment effect variability.By coupling DT with the analysis model, trial sample size can be reduced.DT technology was accepted by the U.S. Food and Drug Administration and European Medicines Agency for applications in clinical trials.},
}

@article {pmid41281561,
year = {2025},
author = {Melamed, I and Buckley, C and Bayko, ME and Williams, JL and Or-Geva, N},
title = {Does C1 esterase inhibitor play a role in post COVID-19 neurological symptoms? A randomized, double-blind, placebo-controlled, crossover, proof-of-concept study.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1523814},
pmid = {41281561},
issn = {1664-2295},
abstract = {BACKGROUND: Many patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience neurologic changes post-infection, which has been hypothesized to be due to dysregulation in the infectious-immune axis that leads to a neuro-immune response. This immune dysfunction has been termed "Alzheimer's of the Immune System" or AIS and there are several immune factors that may play a key role. These include, among others, complement activation due to low levels of C1-esterase inhibitor (C1-INH) and function, and a decrease in signaling of Toll-like receptor (TLR)-3. We propose that C1-INH replacement may upregulate the immune dysfunction, thereby improving neurological symptoms.

METHODS: In this randomized, double-blind, placebo-controlled, crossover, proof-of-concept study, adults experiencing SARS-CoV-2 post-viral fatigue syndrome for >4 weeks post-recovery from coronavirus disease 2019 (COVID-19) infection were randomized 1:1 to two arms: Arm 1 (C1-INH for 8 weeks, then placebo for 8 weeks) or to Arm 2 (placebo for 8 weeks, then C1-INH for 8 weeks). Patients were assessed for adult executive function, abnormal cognitive decline, depression [Beck Depression Inventory-II (BDI-II)], migraine, fatigue [Fatigue Severity Scale (FSS)] and pain (Short-form McGill Pain Questionnaire). Percent change in TLR signaling in response to zymosan was compared with controls at baseline, Week 8 and Week 16. Safety was assessed throughout.

RESULTS: At this interim analysis, 36 patients with SARS-CoV-2 post-viral fatigue syndrome had completed the two 8-week treatment periods. In Arm 1, trends toward improvements from baseline at Week 8 of C1-INH therapy were observed in BDI-II score (-8.7 points), mean FSS score (0.6 points), and mean McGill Pain Questionnaire score (-0.4 points). These improvements were either sustained or worsened at Week 16, following crossover to placebo. The outcomes in Arm 2 were compatible with those in Arm 1. Patients with SARS-CoV-2 post-viral fatigue syndrome had low levels of TLR-related signaling biomarkers compared with healthy controls.

CONCLUSION: This proof-of-concept study demonstrates sustained dysregulation of the immune system after COVID-19 infection. Improvements in depression, fatigue, and pain were observed with C1-INH treatment in patients with SARS-CoV-2 post-viral fatigue syndrome, indicating C1-INH may be a potential therapeutic target.

CLINICAL TRIAL REGISTRATION: The study was registered on September 21, 2024, with the identifier number NCT04705831.},
}

@article {pmid41281560,
year = {2025},
author = {Sun, Q and Wang, F},
title = {Using artificial intelligence and radiomics to analyze imaging features of neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1624867},
pmid = {41281560},
issn = {1664-2295},
abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterized by complex, multifactorial progression patterns that challenge early diagnosis and personalized treatment planning.

METHODS: To address this, we propose an integrated AI-radiomics framework that combines symbolic reasoning, deep learning, and multi-modal feature alignment to model disease progression from structural imaging and behavioral data. The core of our method is a biologically informed architecture called NeuroSage, which incorporates radiomic features, clinical priors, and graph-based neural dynamics. We further introduce a symbolic alignment strategy (CAIS) to ensure clinical interpretability and cognitive coherence of the learned representations.

RESULTS AND DISCUSSION: Experiments on multiple datasets-including ADNI, PPMI, and ABIDE for imaging, and YouTubePD and PDVD for behavioral signals-demonstrate that our approach consistently outperforms existing baselines, achieving an F1 score of 88.90 on ADNI and 85.43 on PPMI. These results highlight the framework's effectiveness in capturing disease patterns across imaging and non-imaging modalities, supporting its potential for real-world neurodegenerative disease monitoring and diagnosis.},
}

@article {pmid41281523,
year = {2025},
author = {Li, YP and Niu, Y and Ding, H and Chen, Z and Zhang, Q},
title = {Potential role of meningeal lymphatic drainage in repetitive transcranial magnetic stimulation-induced cognitive improvement: A call for further research.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {111985},
pmid = {41281523},
issn = {2220-3206},
abstract = {Mild cognitive impairment (MCI), which is a high-risk transitional phase leading to Alzheimer's disease, is characterized by mild memory deficits and specific cognitive dysfunctions. Without effective intervention, a significant proportion of patients with MCI progress to dementia. However, current pharmacological treatments are characterized by side effects and poor patient compliance. Therefore, it is necessary to develop effective, noninvasive alternative treatments. Repetitive transcranial magnetic stimulation (rTMS) is becoming a widely studied noninvasive treatment for central nervous system disease. The therapeutic effects of rTMS on patients with MCI and its underlying mechanism are noteworthy issues. Recently, a growing number of studies have shown that meningeal lymphatic vessel damage may be related to cognitive dysfunction. Whether the improvement of the meningeal lymphatic system is an important mechanism through which rTMS improves the clinical manifestations of MCI is worthy of further study.},
}

@article {pmid41281504,
year = {2025},
author = {Teixeira, AL and Kim, Y and Cordeiro, TM and de Erausquin, GA and Rocha, NP},
title = {Agitation in Alzheimer's disease: From assessment to therapeutics.},
journal = {World journal of psychiatry},
volume = {15},
number = {11},
pages = {109581},
pmid = {41281504},
issn = {2220-3206},
abstract = {Agitation is a neuropsychiatric syndrome characterized by excessive motor and/or verbal behaviors, with or without aggressive behaviors. The prevalence of agitation in Alzheimer's disease varies from 5% to over 50%. Multiple factors have been implicated in its pathophysiology, including disease stage, comorbidity with other symptoms (e.g., psychosis, anxiety/depression), and psychosocial factors. Ruling out delirium and identifying environmental triggers are fundamental steps in the management of agitation in Alzheimer's disease. For establishing an effective therapeutic plan, it is important to define duration, severity, and potential for harm. While non-pharmacological approaches are considered the first line of intervention, pharmacological agents are frequently used in the treatment of agitation. Antipsychotics are commonly used in acute agitation. For chronic agitation, serotonin-selective reuptake inhibitors, especially citalopram and escitalopram, are often preferred due to safety concerns associated with the long-term use of antipsychotics. Promising novel strategies, such as new compounds and neuromodulation, are likely to be incorporated into agitation therapeutics in the next few years.},
}

@article {pmid41281281,
year = {2025},
author = {Jing, S and Wang, Y and Liu, Y and Luo, Y and Wen, X and Ma, Y and Zhu, H and Chen, G and Ouyang, X},
title = {Folic acid as a potential therapeutic agent for Alzheimer's disease: Effects on inflammatory cytokines, amyloid deposition, and neurotransmitter metabolism.},
journal = {Journal of medical biochemistry},
volume = {44},
number = {7},
pages = {1551-1557},
pmid = {41281281},
issn = {1452-8258},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by neuroinflammation and amyloid deposition. Folic acid (FA), a B vitamin, may improve the course of AD by modulating inflammation and neuroprotection. This study aimed to investigate the effects of FA supplementation on serum inflammatory cytokines (IL-1b, IL-6, TNF-a), amyloid (Ab1-42), Tau proteins, and neurotransmitters (GABA, 5-HT, Ach) in AD patients.

METHODS: We conducted a follow-up-controlled trial; 114 AD patients were included and randomly divided into a control group (donepezil treatment) and an experimental group (donepezil + FA treatment) for 3 months. Inflammatory factors, Ab1-42, Tau, neurotransmitter levels and nutritional status were assessed before and after treatment.

RESULTS: The total effective rate of the experimental group (89.47%) was significantly higher than that of the control group (75.44%), and the levels of inflammatory factors (IL-1b, IL-6, and TNF-a), Ab1-42, and Tau were significantly lower (P<0.05), and neurotransmitters (GABA, 5-HT, and Ach) and nutritional indexes (albumin and hemoglobin) were substantially higher.

CONCLUSIONS: FA supplementation can effectively delay AD progression by inhibiting neuroinflammation, reducing amyloid deposition, regulating neurotransmitter metabolism and improving nutritional status.},
}

@article {pmid41280486,
year = {2025},
author = {Taube, PS and Fernandes, D and Vasconcelos, AA and Costa, JAS and de Araujo, MP and Lima, AKO and Wahab, N and Dos Santos, EKL and de Oliveira, MI and da Silva, JP and Andriani, KF and da Silva Oliveira, TP and Sampaio, MC and de Campos Braga, H and de Araújo, ACS and Gul, K},
title = {Perspectives and state-of-the-art use of metal-derived, porous nanomaterials and metallo-drugs for biomedical applications.},
journal = {3 Biotech},
volume = {15},
number = {12},
pages = {416},
pmid = {41280486},
issn = {2190-572X},
abstract = {Due to a combination of genetic, environmental, and behavioral factors, the number of infectious and non-infectious diseases affecting humans has been rising. Many illnesses are in the forefront of research and development such as neoplasms of different forms, chronic conditions related to inflammation and lifestyle (e.g., cancer, diabetes mellitus, Alzheimer's and Parkinson's diseases) and infectious diseases that are difficult to treat (e.g., due to drug resistance). Due to current challenges in diagnosis and treatment of diseases and health conditions, the field of nanotechnology has witnessed numerous advancements. In particular, metal-based, porous nanomaterials and metallo-drugs have gained attention due to their ability to be used for various diagnostic and therapeutic applications. These systems exhibit excellent physicochemical properties, with amenable functionalization and varying optical, scattering and electronic properties, enabling for both imaging and therapy of diseases (i.e., theranostics), involving techniques such as photoacoustic imaging, magnetic resonance imaging (MRI), computed tomography (CT), photothermal therapy (PTT), photodynamic therapy (PDT) and radiotherapy. This review discusses the important aspects of metal nanoparticles, porous-based materials and metallo-drugs for biomedical applications, exploring their physical and chemical characteristics, cellular/molecular processes and biopotencies that make them effective in treating a variety of illnesses or diseases.},
}

@article {pmid41280332,
year = {2025},
author = {Wu, Z and Yu, S and Tian, D and Cheng, L and Jing, J},
title = {Microglial TREM2 and cognitive impairment: insights from Alzheimer's disease with implications for spinal cord injury and AI-assisted therapeutics.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1705069},
pmid = {41280332},
issn = {1662-5102},
abstract = {Cognitive impairment is a frequent but underrecognized complication of neurodegenerative and traumatic central nervous system disorders. Although research on Alzheimer's disease (AD) revealed that microglial triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in inhibiting neuroinflammation and improving cognition, its contribution to cognitive impairment following spinal cord injury (SCI) is unclear. Evidence from AD shows that TREM2 drives microglial activation, promotes pathological protein clearance, and disease-associated microglia (DAM) formation. SCI patients also experience declines in attention, memory, and other functions, yet the specific mechanism of these processes remains unclear. In SCI, microglia and TREM2 are involved in inflammation and repair, but their relationship with higher cognitive functions has not been systematically examined. We infer that TREM2 might connect injury-induced neuroinflammation in the SCI with cognitive deficits, providing a new treatment target. Artificial intelligence (AI) offers an opportunity to accelerate this endeavor by incorporating single-cell transcriptomics, neuroimaging, and clinical data for the identification of TREM2-related disorders, prediction of cognitive trajectories, and applications to precision medicine. Novel approaches or modalities of AI-driven drug discovery and personalized rehabilitation (e.g., VR, brain-computer interface) can more precisely steer these interventions. The interface between lessons learned from AD and SCI for generating new hypotheses and opportunities for translation.},
}

@article {pmid41280310,
year = {2025},
author = {Inamdar, A and Bugadannavar, P and Palled, M and Umarani, S and Salve, P and Gurupadayya, B and Patil, P and Sharma, H},
title = {Biological determinants of blood-based biomarker levels in Alzheimer's disease: role of nutrition, inflammation, and metabolic factors.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1614962},
pmid = {41280310},
issn = {1663-4365},
abstract = {OBJECTIVES: The review discusses the effect of biological determinants such as nutritional deficiency, systemic inflammation, and metabolic disorders affect blood-based biomarker (BBBM) levels, influencing their use in diagnosing, prognosticating, and treatment in Alzheimer's disease (AD). While the individual contributions of neuroinflammation, brain insulin resistance, and micronutrient deficiencies to AD pathology are well-established, a significant knowledge gap exists in understanding their intricate, synergistic interactions. This review proposes a novel integrated framework of bidirectional crosstalk where these three factors create a self-perpetuating cycle of neurodegeneration.

METHODS: A comprehensive literature review was conducted, including all aspects of epidemiological and biological context associated with vitamins, micronutrients, and dietary patterns; inflammatory cytokines; insulin resistance; metabolic syndrome; and hormonal changes. Emerging integrative approaches such as multi-omics, AI modeling, and systems biology were also reviewed for their possible refinement in biomarker interpretation.

RESULTS: The results prove that the deprivation of vitamins E, D, B12, and antioxidants contributes to oxidative stress and subsequent neuroinflammation that changes levels of blood-based biomarkers. A chronic state of inflammation caused by cytokines like IL-6, IL-18, and TNF-α represents a major link to the formation of increased amyloid plaques and tau tangles. Metabolically deregulated states, such as insulin resistance, dyslipidemia, and thyroid imbalance, further alter variability in biomarkers. All these factors would act together to affect the expression of key biomarkers-Aβ, p-tau, and neurofilament light chain (NFL). Individualized interpretation, stratified clinical trials, and digital monitoring tools are potentially effective for achieving better diagnostic precision and boosting treatment efficacy.

CONCLUSION: To a large extent, factors must all be understood thoroughly from multiple biological angles to improve early diagnosis, risk prevention, and treatment personalization in AD. Future studies should develop integrative models that consider nutrition, metabolism, and inflammation to address and fully exploit biomarker utility as well as support precision medicine approaches.},
}

@article {pmid41280213,
year = {2025},
author = {Ali, SH and Osmaniye, D and Kaplancıklı, ZA},
title = {Synthesis and biological evaluation of novel hydrazone derivatives for the treatment of Alzheimer's disease.},
journal = {RSC advances},
volume = {15},
number = {53},
pages = {45729-45743},
pmid = {41280213},
issn = {2046-2069},
abstract = {In recent years, Alzheimer's disease has emerged as a silent epidemic neurodegenerative disorder. Due to its complex pathophysiology, there has been significant scientific interest in developing effective treatments that go beyond symptomatic relief. The main aim is to improve patients' quality of life and lower the death rate associated with Alzheimer's disease. Since this has not yet been achieved, continued research on Alzheimer's disease remains a global priority. In this study, a total of 27 hybrid molecules (D1a-D1i, D2a-D2i, and D3a-D3i) were designed based on the molecular scaffold of donepezil, a well-known acetylcholinesterase inhibitor (AChEI). These hybrids incorporate dihydrothiazolyl hydrazone and phenyl piperidine moieties. All compounds were synthesized and characterized using IR, NMR, and HRMS spectroscopy, and subsequently evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition using the in vitro Ellman method. Evaluation of biological activity revealed that compound D1f exhibited the highest inhibitory activity against the AChE enzyme, with an IC50 of (0.039 ± 0.001 Mm). In contrast, none of the compounds showed significant inhibitory activity against the BChE enzyme. Cytotoxicity testing of compound D1f on NIH3T3 fibroblast cells demonstrated non-cytotoxic effects (IC50 = 3.324 ± 0.155 µM) and the highest selectivity index (SI = 85.231), respectively. Molecular docking and molecular dynamics simulations verified the stable binding affinity and favorable interactions of compound D1f within the active site of acetylcholinesterase (AChE). The results further demonstrated that the AChE enzyme preserved its structural integrity and compactness throughout its interaction with D1f. Collectively, these observations highlight D1f as a promising lead molecule for subsequent optimization and development of novel anti-Alzheimer's therapeutic agents.},
}

@article {pmid41280038,
year = {2025},
author = {Terzioglu, G and Karp, ES and Heuer, SE and Haage, VC and De Jager, PL and Young-Pearse, TL},
title = {INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.27.684632},
pmid = {41280038},
issn = {2692-8205},
abstract = {INPP5D, the gene encoding SHIP1, is genetically associated with Alzheimer's disease (AD) risk and plays a central role in regulating immune function. Here, we aimed to elucidate the mechanism by which SHIP1 mediates its role in suppressing inflammatory pathways, with a focus on human microglia. Our findings illuminate an essential role for SHIP1 in endosome maturation and lysosomal function. We show that SHIP1 localizes to both the plasma membrane and to endo-lysosomal compartments and binds to the CapZ family of proteins, which are important for endosome maturation. Reduction of SHIP1 levels via genome editing impairs endosome maturation and lysosomal function, leading to lipid droplet accumulation and leakage of lysosomal cathepsin B into the cytosol, which in turn activates the NLRP3 inflammasome. CITE-seq profiling of SHIP1-deficient microglia revealed a shift from an immune-responsive state toward a DAM-like, phagocytic state, accompanied by impaired response to LPS and enhanced phagocytosis of synaptic material and apoptotic neurons via TREM2. While amyloid-β uptake was not affected, amyloid-β accumulated intracellularly due to defective lysosomal degradation, further driving lipid droplet formation. Together, these results identify SHIP1 as a regulator of endo-lysosomal function and selective phagocytosis of lipid-rich substrates in microglia. These findings have important implications for therapeutic hypotheses that target SHIP1 for treatment of AD, autoimmune diseases, and cancer.},
}

@article {pmid41279689,
year = {2025},
author = {Schurman, CA and Kaur, G and Kaya, S and Bons, J and Aguirre, CG and Liu, Q and King, CD and Wilson, KA and Baker, HL and Hady, M and Luna, NM and Bieri, G and Villeda, SA and Ellerby, LM and Schilling, B and Alliston, T},
title = {Alzheimer's disease risk factor APOE4 exerts dimorphic effects on female bone.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.16.682922},
pmid = {41279689},
issn = {2692-8205},
abstract = {Individuals diagnosed with Alzheimer's disease (AD) are at an increased risk of bone fractures. Conversely, a diagnosis of osteoporosis in women is the earliest known predictor for AD. However, mechanisms responsible for the coupled decline in cognitive and skeletal health remain unclear. Proteomic analysis of cortical bone from aged mice revealed neurological disease-associated proteins that are highly enriched in aged mouse bones, including apolipoprotein E (Apoe) and amyloid precursor protein. Further, Apoe localized specifically to bone-embedded osteocytes with expression twice as high in aged female bone as in young or male counterparts. In humans, APOE allele variants carry differing AD risk with age. To investigate APOE allelic roles in bone, we utilized a humanized APOE knock-in mouse model that expresses either the protective APOE2, the neutral APOE3, or the AD risk factor APOE4, and analyzed bone and hippocampus from the same mice. APOE4 exerted strong sex-specific effects on the bone transcriptome and proteome, relative to APOE2 or APOE3. Interestingly, the APOE4-associated perturbation in the female bone proteome was more pronounced than the corresponding alterations observed in the hippocampus. APOE4 protein causes bone fragility in females, but not males, even without changes in cortical bone structure. These bone quality deficits arose from suppression of osteocyte perilacunocanalicular remodeling. We find that APOE4 is a new molecular culprit capable of disrupting osteocyte maintenance of bone quality as early as midlife in a manner that disproportionately affects females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment, and treatment for bone fragility, in females.},
}

@article {pmid41279475,
year = {2025},
author = {Veerareddy, V and Wang, Z and Kashyap, PC and Kandimalla, KK},
title = {Butyrate regulates the blood-brain barrier transport and intra-endothelial accumulation of Alzheimer's disease Amyloid-beta peptides.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.24.684335},
pmid = {41279475},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid beta (Aꞵ) proteins as amyloid plaques, tau aggregates, and cerebrovascular dysfunction that drive disease progression. Butyrate, a gut microbial metabolite, has been found to be reduced in AD patients; butyrate supplementation improved cognition and decreased amyloid burden in animal models. However, the precise underlying mechanisms are unclear. Our previous studies have demonstrated that insulin signaling impacts Aꞵ transport kinetics at the blood-brain barrier (BBB). In this study, we investigated the effect of butyrate treatment on intra-endothelial Aꞵ accumulation and BBB integrity by modulating the insulin signaling pathway. The effect of butyrate on Aꞵ accumulation was assessed by flow cytometry in BBB cell culture models. Insulin signaling activation and the expression of various receptors and transporters at the BBB were evaluated by Western blots and confocal microscopy. The roles of various molecular mediators were confirmed using specific inhibitors (MK2206, Trametinib, Rapamycin, VX-745). The effect of butyrate on the expression of BBB receptors and transporters that play a critical role in Aꞵ trafficking was examined in mouse brains colonized with butyrate-producing bacteria via immunohistochemistry. Butyrate significantly decreased Aβ42 accumulation in endothelial cells. This effect was associated with insulin signaling pathway activation, particularly AKT and ERK phosphorylation. Inhibitor studies established the critical role of these specific arms, as co-incubation with MK2206 (AKT inhibitor) or Trametinib (ERK inhibitor) reversed the protective effect of butyrate and increased Aβ42 accumulation. However, mTOR and p38 inhibitors did not show a similar effect. In addition, butyrate restored P-glycoprotein efflux transporter expression and claudin-5 tight junction protein levels that were reduced with Aβ treatment. These effects were supported by in vivo work, which demonstrated the upregulation of Tissue Inhibitor of Metalloproteinases-2 (TIMP-2). This protein is associated with AKT activation and extracellular matrix stabilization in mice colonized with butyrate-producing bacteria. In conclusion, we have demonstrated that butyrate decreases Aβ42 uptake at the BBB endothelium by activating the AKT and ERK arms of the insulin signaling pathway. These changes may also improve the integrity of BBB tight junctions by increasing claudin-5 expression and extracellular matrix, and by upregulating TIMP-2 expression. This study highlights butyrate's potential as a therapeutic modulator of AD-related BBB dysfunction.},
}

@article {pmid41278376,
year = {2025},
author = {Li, J and Zhang, J and Xu, X and Xiao, L and Ling, Y and Liu, S and Gao, Y and Zhao, L and Jia, H},
title = {Quality and reliability of Alzheimer's disease videos on Douyin and Bilibili: A cross-sectional content analysis study.},
journal = {Digital health},
volume = {11},
number = {},
pages = {20552076251398464},
pmid = {41278376},
issn = {2055-2076},
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a significant public health challenge to China's aging population. Patients and their families increasingly turn to short-video platforms such as Douyin and Bilibili for information. However, there is currently a lack of systematic analysis regarding the quality and reliability of advertising content on these platforms, creating a critical gap in understanding this emerging information ecosystem.

AIM: Systematically evaluate the quality and reliability of videos on Douyin and Bilibili, analyzing the relationship between content themes, upload sources, and user engagement metrics.

METHODS: Using "Alzheimer's disease" as the keyword, we retrieved the top 100 videos from multiple platforms. Videos were categorized by uploader type and content. Two qualified researchers assessed their reliability and quality using the JAMA, the modified DISCERN instrument (mDISCERN), and Global Quality Score (GQS) scale. Data analysis employed nonparametric statistical methods. Apply relevance and logistic regression analysis to discuss factors that may influence video quality.

RESULTS: This study analyzed a total of 171 videos. Results indicate that compared to Douyin, videos on the Bilibili platform scored higher across multiple quality evaluation metrics (GQS: 2.0(1.0-2.0) vs 1.0(1.0-2.0); mDISCERN: 2.0(2.0-2.0) vs. 2.0(2.0-2.0); JAMA: 2.0(1.0-2.0) vs. 1.0 (1.0-2.0); p < 0.001). This disparity may be attributed to Bilibili's longer video format, which allows for more in-depth content, and its user base that tends to favor detailed, knowledge-oriented media. Regarding uploader identity, videos posted by professionals (e.g. physicians) demonstrated superior quality compared to nonprofessional sources (e.g. patients). However, patient-uploaded videos exhibited stronger engagement metrics (e.g. likes, comments). Content-wise, videos focusing on disease prevention and treatment consistently achieved the highest overall quality (all comparisons p < 0.05). Correlation analysis indicated that while interaction metrics showed strong internal correlations, they did not significantly correlate with JAMA, mDISCERN, or GQS scores. Ordered logistic regression analysis indicates that uploader identity, content classification, and presentation format are the three key factors influencing video quality.

CONCLUSION: This study reveals a pronounced "quality-dissemination paradox" in AD content across mainstream short-video platforms: While scientifically rigorous content published by medical professionals receives high quality ratings, it significantly underperforms in user engagement metrics compared to nonprofessional content centered on patient narratives and lived experiences. This highlights a severe disconnect between scientific rigor and public participation within algorithmic dissemination ecosystems. To address this, platforms should optimize algorithms to enhance the visibility of authoritative content, encourage collaboration between professional and nonprofessional creators to boost content appeal, and strengthen health media literacy education for the public-particularly older adults-to improve their ability to discern information.},
}

@article {pmid41278202,
year = {2025},
author = {Larriba-González, T and García-Martín, M and Ojeda-Hernández, DD and Rincón-Cerrada, P and Martín-Blanco, L and Benito-Martín, MS and Selma-Calvo, B and de la Fuente-Martín, S and Matias-Guiu, JA and Matias-Guiu, J and Gómez-Pinedo, U},
title = {Modeling neurodegenerative diseases with brain organoids: from development to disease applications.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1663286},
pmid = {41278202},
issn = {2296-634X},
abstract = {Organoids derived from stem cells have significantly advanced disease modeling, particularly in neurodegenerative disorders, while advancing personalized and regenerative medicine. These three-dimensional structures reproduce key aspects of human brain organization and functionality, while remaining simplified models that do not yet recapitulate full neural circuitry or disease progression, providing an improved platform for studying disease mechanisms, drug responses, and potential therapeutic strategies. This review explores the methodologies used in organoid development, including the differentiation of stem cells and culture techniques that enable the formation of self-organizing tissues. Organoids have been successfully used to model key cellular and molecular aspects of neurodegenerative diseases such as Alzheimer's and Parkinson's, offering insights into early disease mechanisms and potential novel treatment strategies. Key findings highlight that organoids provide more physiologically relevant data than traditional two-dimensional cultures and animal models, making them valuable tools for preclinical research and personalized treatment approaches. However, challenges remain, including variability in organoid generation, lack of vascularization, and difficulties in large-scale production for clinical applications. For the effective integration of organoids into biomedical and clinical applications, future research should prioritize improving reproducibility, standardization, and vascularization methods. Addressing these limitations will enhance their translational potential, leading to more effective treatments for neurodegenerative disorders and broader applications in precision medicine.},
}

@article {pmid41278077,
year = {2025},
author = {Arai, H},
title = {Underestimated Centiloid Values in Amyloid PET: A Technical Report on Clinically Relevant Quantification Errors.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e97398},
pmid = {41278077},
issn = {2168-8184},
abstract = {Quantitative amyloid positron emission tomography (PET) interpretation using the Centiloid scale is increasingly adopted worldwide to guide eligibility and continuation of anti-amyloid monoclonal antibody therapy. However, discrepancies between visual and quantitative assessments occasionally occur, potentially leading to critical misjudgments in clinical decision-making. We present a representative 18F-florbetapir case in which cortical amyloid deposition was visually evident, yet the calculated Centiloid value was 0, falsely indicating a negative scan. This underestimation likely results from reference region selection: using the whole cerebellum (including white matter) lowers standardized uptake value ratios by approximately 7% compared with cerebellar gray matter, thereby decreasing Centiloid values. Consequently, patients with substantial amyloid burden may be incorrectly deemed ineligible for initiation or continuation of anti-amyloid therapy. Clinicians should therefore interpret Centiloid-based quantification with caution, always corroborating it with expert visual reads. Harmonization of reference region definitions and standardized reporting are urgently needed to prevent inappropriate treatment decisions and ensure the safe, effective use of disease-modifying therapies in Alzheimer's disease.},
}

@article {pmid41278048,
year = {2025},
author = {Lin, WC and Wu, A and Chen, NC and Ha, B},
title = {Observations of Triple Network Model Connectivity Changes by Functional Magnetic Resonance Imaging in a Single Early-Stage Dementia Participant Pre- and Post-craniosacral Therapy: A Case Report.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e97329},
pmid = {41278048},
issn = {2168-8184},
abstract = {Resting-state functional magnetic resonance imaging (rs-fMRI) is a noninvasive imaging technique that measures spontaneous brain activity to map functional connectivity within and between brain networks characterized as the triple network model (TNM). In Alzheimer's disease (AD), rs-fMRI has been used to detect early network disruptions, track disease progression, and evaluate therapeutic interventions. While craniosacral therapy (CST) has shown clinical benefits for conditions like chronic pain and migraine, its impact on TNM connectivity in AD, as evidenced by rs-fMRI, has not been explored. This case report involves a 79-year-old man with early-stage AD who presented with mild delusions, anxiety, irritability, and nighttime behaviors and a Mini-Mental State Examination (MMSE) score of 24 and a Clinical Dementia Rating (CRD) of 0.5, indicating a mild neurocognitive disorder. Preliminary rs-fMRI data revealed changes in the default mode network (DMN), salience network (SN), and central executive network (CEN) following CST. These changes suggest greater connectivity within the CEN and SN, alongside reduced variability in the DMN following CST. These observations suggest potential reorganization of TNM dynamics. The clinical relevance of these findings remains under evaluation. The observations from this single case report limit the ability to draw definitive conclusions about the impact of CST on TNM connectivity in early-stage AD. A further study is needed to determine if the TNM changes observed by rs-fMRI can be replicated in additional participants and if the changes are correlated with clinical outcomes. Further studies with larger cohorts, extended treatment durations, and longer follow-up periods are needed to explore the potential clinical benefits of CST in this population.},
}

@article {pmid41277450,
year = {2025},
author = {Wharton, T and Paulson, D and McClure, NV and Laird, RD and Campos, BM and Churchill, EG and Lysandrou, AE and Maynard, M},
title = {Pilot trial of the Florida-Resources for Enhancing Alzheimer's Caregiver Health (FL-REACH) intervention in an outpatient memory disorders clinic.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13607863.2025.2585507},
pmid = {41277450},
issn = {1364-6915},
abstract = {OBJECTIVES: Translation of the foundational REACH II intervention for caregivers of persons with Alzheimer's disease and related dementias (ADRD) into practice has been limited. Most interventions generally focus on later-stage caregiving. The FL-REACH intervention was adapted from REACH II, addressing issues of implementation burden and shifting focus to prolonging in-home care through intervention delivered soon after diagnosis. Goals of this single-arm pilot study were to examine effectiveness of a six-session intervention delivered through an outpatient memory disorders clinic to caregivers of those diagnosed with mild to moderate stage memory disorders.

METHOD: Dementia caregivers were recruited from the AdventHealth Maturing Minds Program. The COVID-19 pandemic compelled transition of the intervention delivery from the clinic environment to online.

RESULTS: Dementia knowledge, caregiver burden, and caregiver preparedness all improved from baseline to post-treatment. Participants who completed the intervention online were disproportionately male, and more socioeconomically and ethnically diverse than those who completed the intervention in person.

CONCLUSION: Results support use of the FL-REACH intervention program and suggest that memory disorders clinics create a valuable opportunity for enrollment in dementia caregiver interventions that provide training and skills development early in the disease trajectory.},
}

@article {pmid41277070,
year = {2025},
author = {Casagrande, LR and Medeiros, EB and Venturini, LM and Zaccaron, RP and da Costa, C and Bittencourt, JVS and Modolon, HB and Lidio, AV and Arcaro, S and Budni, J and Gu, Y and Thirupathi, A and Lock Silveira, PC},
title = {Neuromodulation with low-intensity pulsed ultrasound (Lipus) combined with curcumin-gold nanoparticles (Cur-AuNPs) in an Alzheimer's disease model.},
journal = {Drug delivery},
volume = {32},
number = {1},
pages = {2577826},
doi = {10.1080/10717544.2025.2577826},
pmid = {41277070},
issn = {1521-0464},
mesh = {Animals ; *Alzheimer Disease/drug therapy/therapy/metabolism ; *Curcumin/administration & dosage/pharmacology/chemistry ; *Gold/chemistry/administration & dosage ; Mice ; *Metal Nanoparticles/chemistry/administration & dosage ; Male ; Disease Models, Animal ; Amyloid beta-Peptides ; Maze Learning/drug effects ; Ultrasonic Waves ; Peptide Fragments ; Hippocampus/metabolism/drug effects ; Blood-Brain Barrier/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that requires innovative therapeutic strategies. This is the first study to evaluate the synergistic effects of LIPUS and CUR-AuNPs in an AD model, which aimed to investigate the effects of these therapies on learning, memory and neuroinflammation in mice with β-amyloid peptide (βA1-42)-induced AD. Sixty mice were divided into five groups: control, βA1-42, βA1-42 + LIPUS, βA1-42 + CUR-AuNPs, and βA1-42 + LIPUS + CUR-AuNPs. Treatments began 24 hours after induction and continued for 17 days using intranasal CUR-AuNPs (25 μg/mL) and transcranial LIPUS (0.8 W/cm[2], 1 MHz). The results demonstrated that the isolated therapies reversed memory deficits in the Y-maze and radial maze tests. However, the combined therapy group was able to reverse these deficits only in the radial maze. Electron microscopy confirmed the ability of CUR-AuNPs to cross the blood‒brain barrier, especially in the combined group, and no liver toxicity was observed. All the treated groups presented increased BDNF in the hippocampus and cortex. IL-1β and IL-6 levels are reduced in the cortex, while IL-1β and TNF-α levels are decreased in the hippocampus. IL-10 increased only in the hippocampus, while GSH levels increased in both regions. Combination therapy also reduced nitrite concentrations in the hippocampus and cortex and NFκB expression in the hippocampus. APP expression decreased exclusively in the LIPUS group in the hippocampus. These results suggest that although single treatments are effective, their combination enhances neuroprotective responses through the modulation of inflammation, oxidative stress, and neurotrophic signaling, suggesting promising potential for AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/therapy/metabolism
*Curcumin/administration & dosage/pharmacology/chemistry
*Gold/chemistry/administration & dosage
Mice
*Metal Nanoparticles/chemistry/administration & dosage
Male
Disease Models, Animal
Amyloid beta-Peptides
Maze Learning/drug effects
Ultrasonic Waves
Peptide Fragments
Hippocampus/metabolism/drug effects
Blood-Brain Barrier/metabolism

@article {pmid41276859,
year = {2025},
author = {Noguchi-Shinohara, M and Yoshinobu, T and Ozaki, T and Muramatsu, D and Shima, A and Sakashita, Y and Tada, Y and Yamaguchi, H and Komatsu, J and Ikeda, T and Ono, K},
title = {Higher phosphorylated tau levels predict cognitive decline and amyloid-related imaging abnormalities during lecanemab treatment: clinical practice data.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {251},
pmid = {41276859},
issn = {1758-9193},
mesh = {Humans ; Female ; Male ; Aged ; *tau Proteins/metabolism/cerebrospinal fluid ; *Cognitive Dysfunction/drug therapy/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Phosphorylation ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Biomarkers/cerebrospinal fluid/blood ; Middle Aged ; Aged, 80 and over ; Brain/diagnostic imaging ; Positron-Emission Tomography ; Neuropsychological Tests ; *Plaque, Amyloid/diagnostic imaging/drug therapy ; },
abstract = {BACKGROUND: Lecanemab was recently approved for the treatment of patients with early Alzheimer's disease (AD) and demonstrated reduced senile amyloid plaque and less decline on the measures of cognition and function in clinical trials. However, the real-world data on its efficacy and safety remain limited. We aimed to evaluate the effectiveness and tolerance of lecanemab treatment and determine biomarkers at baseline that could predict cognitive deterioration and the occurrence of amyloid-related imaging abnormaities (ARIA) in real-world clinical practice.

METHODS: To determine the indication for lecanemab, the patients were evaluated through neurological examinations, cognitive assessments, blood test, head magnetic resonance imaging (MRI), amyloid positron emission tomography, lumbar puncture, genetic testing, and clinical conferences. The Mini-Mental State Examination (MMSE) was used to assess cognition, and the MRI scans were used for safety monitoring of ARIA.

RESULTS: Between January 2024 and October 2025, 234 patients were screened, 100 initiated lecanemab treatment. The mean age was 72.7 years, and 68 (68.0%) patients were female. Among the 71 patients surveyed via MRI prior to the 14th infusion, 12 (16.9%) had ARIA detected. Compared with those of patients without ARIA, the baseline cerebrospinal fluid (CSF)-ptau181 levels of patients with ARIA significantly increased. When the patients were divided into high and low CSF-ptau181 groups according to the cutoff value (78.6 pg/ml) which derived from ROC analysis for ARIA prediction, the MMSE scores of the high ptau group were significantly declined compared to that of the low ptau group at 6 and 12 months after baseline. The infusion-reactions occurred only in 6.0% of patients. The longitudinal observation revealed that the plasma thrombomodulin levels significantly decreased after 6 months of lecanemab treatment.

CONCLUSION: Lecanemab was generally well tolerated by most patients with early AD and treatment appeared to be more effective and safer in patients with low CSF-ptau181 levels.　Our results suggest an association between lecanemab treatment and reduced markers of vascular endothelial injury.},
}

Humans
Female
Male
Aged
*tau Proteins/metabolism/cerebrospinal fluid
*Cognitive Dysfunction/drug therapy/diagnostic imaging/metabolism
Magnetic Resonance Imaging
Phosphorylation
*Alzheimer Disease/drug therapy/diagnostic imaging
Biomarkers/cerebrospinal fluid/blood
Middle Aged
Aged, 80 and over
Brain/diagnostic imaging
Positron-Emission Tomography
Neuropsychological Tests
*Plaque, Amyloid/diagnostic imaging/drug therapy

@article {pmid41276781,
year = {2025},
author = {Gürbüz, P and Doğan, ŞD and Gündüz, MG and Martínez-González, L and Pérez, C and Martinez, A},
title = {Screening Natural Phenolic Compounds for Blood-Brain Barrier Permeability, Alongside GSK-3β, CK-1δ, and AChE Inhibition, for the Treatment of Alzheimer's Disease.},
journal = {Drug development research},
volume = {86},
number = {8},
pages = {e70193},
doi = {10.1002/ddr.70193},
pmid = {41276781},
issn = {1098-2299},
support = {//The present study was supported by the Research Foundation of Erciyes University (Grant No: TSA-2022-11539)./ ; },
mesh = {*Alzheimer Disease/drug therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/pharmacokinetics ; *Neuroprotective Agents/pharmacology/pharmacokinetics/chemistry ; Molecular Docking Simulation ; *Phenols/pharmacology/chemistry ; Acetylcholinesterase/metabolism ; Permeability ; },
abstract = {Alzheimer's Disease (AD) is a neurological disorder characterized by progressive cognitive impairment and memory loss. In vitro artificial membrane permeability assays targeting the blood-brain barrier (BBB), such as the parallel artificial membrane permeability assay (PAMPA), are useful for pre-evaluating the BBB penetration of molecules during the early stages of drug development. Inhibitors of glycogen synthase kinase-3β (GSK-3β), casein kinase-1δ (CK-1δ), and acetylcholinesterase (AChE) exhibit neuroprotective effects, indicating a potential therapeutic approach for AD. This study aimed to assess the ability of 23 phenolic compounds derived from natural sources to penetrate the central nervous system (CNS) and examine their potential neuroprotective effects. Following the prediction of BBB penetration of the compounds by PAMPA, neuroprotective effects of CNS+ compounds were evaluated through in vitro inhibition of GSK-3β, CK-1δ, and AChE. Based on the data obtained, five flavonoids (hispidulin, nepetin, platanoside, apigenin, and kaempferol) and two furanocoumarins (isopimpinellin and bergapten) were predicted to penetrate the CNS. Apigenin (API) and kaempferol (KEM) exhibited the most potent dual inhibitory activity against CK-1δ and GSK-3β. Furthermore, API and KEM did not exhibit cytotoxic effects in SH-SY5Y cells. Molecular modeling studies, including molecular docking, molecular dynamics simulations, and dynophore analysis, were performed to understand the binding mechanism of these most potent compounds to their target enzymes. Overall, the current study offers a rational approach to designing new molecules inspired by natural compounds to treat Alzheimer's Disease.},
}

*Alzheimer Disease/drug therapy
*Blood-Brain Barrier/metabolism/drug effects
Humans
*Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism
*Cholinesterase Inhibitors/pharmacology/chemistry/pharmacokinetics
*Neuroprotective Agents/pharmacology/pharmacokinetics/chemistry
Molecular Docking Simulation
*Phenols/pharmacology/chemistry
Acetylcholinesterase/metabolism
Permeability

@article {pmid41276735,
year = {2025},
author = {Aghababaee, L and Farrokhi, K and Karimi-Jafari, MH and Shahpasand, K and Riazi, GH},
title = {Cross-Talk Between Tau O-GlcNAcylation and the Formation of the Early Driver of Neurodegeneration (Cis P-Thr231-Pro Tau) in Primary Cortical Neurons.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {158},
pmid = {41276735},
issn = {1559-1182},
mesh = {*tau Proteins/metabolism ; *Neurons/metabolism/pathology/drug effects ; Animals ; *Cerebral Cortex/pathology/metabolism ; Phosphorylation/drug effects ; *Acetylglucosamine/metabolism ; Cells, Cultured ; *Nerve Degeneration/metabolism/pathology ; Thiazoles/pharmacology ; Humans ; Pyrans ; },
abstract = {Tau is a microtubule-associated protein. Hyperphosphorylation of tau at neurotoxic sites, particularly at Thr231 within the Thr231-Pro motif, is a pathological hallmark of Alzheimer's disease (AD) and other tauopathies. Phosphorylated tau at Thr231 exists in two distinct conformations: cis and trans. The Cis pThr231-Pro Tau confomer is neurotoxic and promotes neurodegeneration. Furthermore, tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and it has been suggested that O-GlcNAcylation of tau can influence tau phosphorylation. In this study, we utilized Thiamet G, an O-GlcNAcase (OGA) inhibitor, to elevate tau O-GlcNAcylation levels. Our findings demonstrate that treatment of nutrient-deprived primary cortical neurons with this OGA inhibitor increased tau O-GlcNAcylation, inhibited the formation of the neurotoxic Cis p-Tau conformation, and reduced neuronal cell loss. Additionally, we observed that the Trans p-Tau conformation represents a normal conformer under physiological conditions. Collectively, our data support tau O-GlcNAcylation as a promising therapeutic strategy for Alzheimer's disease and other tauopathies.},
}

*tau Proteins/metabolism
*Neurons/metabolism/pathology/drug effects
Animals
*Cerebral Cortex/pathology/metabolism
Phosphorylation/drug effects
*Acetylglucosamine/metabolism
Cells, Cultured
*Nerve Degeneration/metabolism/pathology
Thiazoles/pharmacology
Humans
Pyrans

@article {pmid41276165,
year = {2025},
author = {Bei, Y and Zhong, D and Lu, J and Qiu, Y and Bowen, TS and Chen, N and Dun, Y and Gao, F and Huang, Y and Li, G and Li, J and Li, J and Liu, F and Liu, W and Ma, X and Rosenzweig, A and Spanos, M and Tian, Z and Yin, P and Wang, R and Wang, Y and Xu, D and Xu, L and Zhang, L and Zhang, J and Zhang, X and Zhou, Q and Qiao, Y and Xu, M and Xiao, J},
title = {Expert consensus statement for basic research of animal exercise intervention studies in chronic disease prevention and treatment: A joint position paper of the Exercise Science branch of the Biophysical Society of China and the Metabolism and Genetics branch of the Genetics Society of China.},
journal = {Journal of sport and health science},
volume = {},
number = {},
pages = {101103},
doi = {10.1016/j.jshs.2025.101103},
pmid = {41276165},
issn = {2213-2961},
abstract = {Chronic diseases, broadly defined as long-duration conditions that require sustained medical care and/or limit activities of daily living, are a major problem that threatens human health and imposes large social and economic burdens. Physical activity has many beneficial effects for human health and is among the most cost-effective ways to prevent and treat chronic diseases. Animal exercise intervention studies are widely used and provide valuable scientific evidence about the cellular and molecular mechanisms underlying the effects of exercise training in a variety of chronic disease models. This consensus statement will provide expert opinions and recommendations for the appropriate design and application of animal exercise intervention studies and models in fundamental investigations of prevention and treatment of chronic diseases, especially focusing on cardiovascular and cerebrovascular diseases (coronary artery disease and stroke), metabolic diseases (obesity and type 2 diabetes mellitus), chronic respiratory diseases (chronic obstructive pulmonary disease), and neurological diseases (Alzheimer's disease). This statement highlights various exercise models (as determined by frequency, intensity, time, and type of exercise intervention) utilized for each disease. Additionally, it includes a list of functional, structural, biochemical, and disease-specific evaluation metrics of exercise effects, followed by outlined recommendations for the exercise study design and evaluations for the mentioned chronic diseases. This consensus aimed to offer practical recommendations for better design and conduct of fundamental research in animal exercise intervention studies to improve our understanding of the effects of exercise on chronic diseases, and to further develop physical exercise or exercise-mimetic interventions for disease prevention and treatment.},
}

@article {pmid41276485,
year = {2025},
author = {Terao, I and Kodama, W},
title = {Comparative Efficacy and Tolerability of Multiple Antipsychotics Across Varying Doses for Neuropsychiatric Symptoms of Dementia Including Alzheimer's Disease: A Dose-Response Model-Based Network Meta-Analysis.},
journal = {Acta psychiatrica Scandinavica},
volume = {},
number = {},
pages = {},
doi = {10.1111/acps.70051},
pmid = {41276485},
issn = {1600-0447},
abstract = {BACKGROUND: Antipsychotics are widely used for neuropsychiatric symptoms (NPSs) in dementia including Alzheimer's disease (AD), yet balancing efficacy and safety remains a major clinical challenge.

METHODS: Relevant randomized controlled trials were identified through a comprehensive literature search of CENTRAL, PubMed, CINAHL, and ClinicalTrials.gov. We conducted a dose-response model-based network meta-analysis to evaluate the efficacy as the change in overall NPS severity and the tolerability as treatment discontinuation due to adverse events of aripiprazole, brexpiprazole, risperidone, quetiapine and olanzapine at varying doses in patients with dementia including AD.

RESULTS: Twenty trials involving 5844 participants were included. Most of the included antipsychotics exhibited a generally positive dose-response relationship with respect to both efficacy and tolerability, except for olanzapine, which showed a bell-shaped curve in terms of efficacy. Only aripiprazole 10 mg, brexpiprazole 1-2.5 mg, risperidone 1-2 mg, and olanzapine 2.5-5 mg were significantly more effective than placebo. Tolerability did not significantly decrease compared to placebo for aripiprazole up to 10 mg, brexpiprazole up to 3 mg, risperidone up to 1 mg, olanzapine up to 2.5 mg and at 15 mg, and quetiapine up to 200 mg. Furthermore, significant differences in efficacy and tolerability were observed between certain doses of several antipsychotics.

CONCLUSIONS: Aripiprazole 10 mg, brexpiprazole 1-2.5 mg, risperidone 1 mg, and olanzapine 2.5 mg were both effective and well tolerated, indicating their potential as favorable treatment options. As the present model incorporates several sources of uncertainty, its findings should be interpreted with caution and regarded as a provisional framework to support clinical decision-making.},
}

@article {pmid41275722,
year = {2025},
author = {Xu, Y and Li, N and Li, X and Cui, X and Ju, R and Li, M and Zhao, J and Han, F},
title = {Integrated analysis strategies reveal the pharmacodynamic substances and action mechanisms of Huangqi San in the treatment of Alzheimer's disease.},
journal = {Journal of pharmaceutical and biomedical analysis},
volume = {270},
number = {},
pages = {117251},
doi = {10.1016/j.jpba.2025.117251},
pmid = {41275722},
issn = {1873-264X},
abstract = {Alzheimer's disease (AD), as a neurodegenerative disorder characterized primarily by memory impairment in its early stages, imposes a heavy burden on society and medical resources. This study aims to investigate the therapeutic effect of Huangqi San (HQS) on AD and elucidate its potential mechanism of action. This study analyzed the rat serum after treated by HQS using UHPLC-Q-Exactive Orbitrap MS, and identified the potential active components of HQS. Subsequently, key targets and pathways were identified through network pharmacology and molecular docking techniques, and were verified in PC12 cells damaged by Aβ25-35. The verification methods included cell viability assays, analysis of inflammatory/oxidative stress markers, and regulation of the PI3K/AKT/MAPK pathway. The results showed that a total of 40 serum adsorption components and 70 common targets were identified. Network analysis revealed that the PI3K-AKT, MAPK and Rap1 signaling pathways were at the core of the network. Molecular docking demonstrated strong binding affinity between 10 core components (e.g., isoliquiritigenin, moracin M) and pivotal targets (BCL2, MAPK3, PTGS2). In vitro validation showed HQS significantly attenuated Aβ25-35-induced neurotoxicity by enhancing cell viability, suppressing apoptosis, reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and oxidative markers (MDA, ROS, CYP2E1) while elevating GSH-Px activity. Moreover, HQS can bidirectionally regulate PI3K/AKT/MAPK pathways via upregulating PI3K/AKT/ERK1/2 and inhibiting JNK/p38 phosphorylation. In conclusion, this study innovatively established HQS as a multi-component/multi-target candidate drug for the treatment of AD. Its mechanism of action is related to its synergistic regulation of PI3K/AKT/MAPK-mediated neuroprotection. This comprehensive approach provides an example for interpreting complex traditional Chinese herbal preparations.},
}

@article {pmid41274321,
year = {2025},
author = {Chu, CT and Uruno, A and Suzuki, T and Taguchi, K and Baird, L and Katsuoka, F and Yamamoto, M},
title = {NRF2 Activation by CDDO-Im Regulates Inflammatory and Autophagy Pathways in Human Microglial Cells.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.11.046},
pmid = {41274321},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, accompanied by elevated oxidative stress and inflammation. Microglia, the resident macrophages in the brain, play a key protective role by clearing plaques and damaged neurons. NRF2 (Nuclear factor erythroid 2-related factor 2) is a master regulator of cytoprotection against oxidative stress, whose activation alleviates oxidative damage, neuroinflammation, and cognitive deficits in AD models. However, direct targets of NRF2 in microglia remain unclear. In this study, we demonstrate that NRF2 activation by CDDO-Im significantly suppresses inflammation in human microglial cells (HMC3) stimulated by IFN-γ or Aβ. Through integrative RNA-sequencing and ChIP-sequencing analysis of NRF2, we identified five representative direct NRF2 target genes involved in inflammation (e.g., IL6, CDK6) and another five related to autophagy (e.g., TFE3, SQSTM1). Importantly, we also found that CDDO-Im treatment enhances autophagy as evidenced by an increased LC3-II/LC3-I ratio. Public single-cell transcriptomic data further underscored the critical role of microglia in NRF2-mediated autophagy regulation within AD brains. Together, our findings reveal new direct NRF2 target genes, highlight the dual role of NRF2 in suppressing inflammation and enhancing autophagy, and thus provide novel insights for therapeutic interventions in AD.},
}

@article {pmid41274317,
year = {2025},
author = {Anbaraki, A and Ghasemi, A and Seyedarabi, A and Yousefi, R and Saboury, AA},
title = {Dual glycation and oxidation of tau protein: Impact of methylglyoxal and hydrogen peroxide on tau structure and fibril assembly.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.11.044},
pmid = {41274317},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) indicate overlapping pathogenic mechanisms including, protein glycation and oxidative stress. Tau protein, a key player in AD pathology, undergoes various post-translational modifications, disturbing its physiological function and facilitating its aggregation/fibrillation. Nevertheless, the cumulative influence of glycation and oxidation on the structural integrity and fibrillation of tau remains inadequately elucidated. In this study, we examined the effects of methylglyoxal (MGO)-induced glycation and hydrogen peroxide (H2O2)-mediated oxidation, individually or in combination, on tau structure, fibrillation and cytotoxicity. Structural and morphological alterations were evaluated using SDS-PAGE, fluorescence spectroscopy, circular dichroism, dynamic light scattering, Fourier transform infrared spectroscopy, and atomic force microscopy. Fibrillation kinetics were monitored under two conditions: (i) pre-fibrillation modification and (ii) simultaneous modification and fibrillation. Our results indicated that the co-treatment with MGO and H2O2 synergistically altered tau structure. Moreover, the fibrillation kinetics of pre-modified tau samples with MGO indicated a reduction in fibrillation through the generation of oligomeric species. Conversely, the fibrillation kinetics of pre-modified tau samples with H2O2 and both compounds increased tau fibrillation. On the other hand, simultaneous modification and fibrillation of tau samples with MGO and H2O2 resulted in an increase in tau fibrillation and structural changes. Collectively, our results indicated that co-treatment with MGO and H2O2 synergistically enhanced tau fibrillation and produced more ordered fibril structures with increased cytotoxicity toward SH-SY5Y cells. These findings provide mechanistic insights into how glycation and oxidative stress cooperatively modulate tau fibrillation and offer a molecular basis for the pathological link between diabetes and AD.},
}

@article {pmid41274188,
year = {2025},
author = {Khan, Y and Naeem, MU and Arooj, K and Naseem, M and Adnan, R and Azmatullah, },
title = {A comprehensive computational and experimental study of novel imidazole linked thiadiazole based amide derivatives as cholinesterase duel-target inhibitor for the treatment of Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {120},
number = {Pt 1},
pages = {108789},
doi = {10.1016/j.compbiolchem.2025.108789},
pmid = {41274188},
issn = {1476-928X},
abstract = {The thiadiazole scaffold has gained prominence in modern drug discovery due to its remarkable structural adaptability. Its unique framework enables interactions with a wide spectrum of biological targets, making it a valuable pharmacophore for therapeutic development. Reflecting its growing clinical importance, efficient synthetic access to thiadiazole derivatives has become a focal point for medicinal chemists seeking to exploit its multifunctional activity. In our study, we synthesized a streamlined and high-throughput synthetic protocol to generate a novel library of imidazole linked thiadiazole analogues. All newly imidazole linked thiadiazole analogues were spectroscopically characterized by [1]HNMR and [13]CNMR spectroscopy and high-resolution electron impact mass spectrometry (HRMS). Biological screening across a panel of key metabolic enzymes revealed potent inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Remarkably, a majority of tested compounds outperformed standard inhibitors donepezil exhibited compounds 1, 2, 4 and 8 showing lower IC50 values of 5.32 ± 0.87 µM (AChE), 6.09 ± 0.97 µM (BuChE), 7.40 ± 0.76 µM (AChE), 6.97 ± 0.56 µM (BuChE), 7.56 ± 0.54 µM (AChE), 7.03 ± 0.39 µM (BuChE), and 5.13 ± 0.28 µM (AChE), 5.33 ± 0.61 µM (BuChE) respectively. Detailed structure-activity relationship (SAR) analyses revealed that strategic substitution patterns modulate inhibitory efficacy and selectivity. Complementing these findings, molecular docking study illuminated key interactions within the catalytic pockets of (AChE) and (BuChE), identifying critical amino acid residues mediating ligand engagement. Hence, our integrated synthetic, biochemical, and computational approach identifies compounds 1, 2, 4 and 8 as a promising lead compound that possess favorable pharmacological attributes for further preclinical development in metabolic disease interventions.},
}

@article {pmid41273473,
year = {2025},
author = {Yang, Z and Peng, X and Zhang, X and Guo, H and Li, Z and Wu, X and Zhao, M and Ruganzu, JB and Zhai, C and Ji, S and Yang, W},
title = {Tanshinone IIA Promotes Hippocampal Neurogenesis in ApoE[-/-] Mice Through cAMP/PKA/CREB/BDNF Signaling Pathway.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {144},
pmid = {41273473},
issn = {1559-1182},
support = {2023-JC-YB-735//the Natural Science Basic Research Plan in Shaanxi Province of China/ ; },
mesh = {Animals ; *Neurogenesis/drug effects ; *Brain-Derived Neurotrophic Factor/metabolism ; *Hippocampus/drug effects/metabolism ; *Signal Transduction/drug effects ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Cyclic AMP/metabolism ; *Cyclic AMP-Dependent Protein Kinases/metabolism ; *Abietanes/pharmacology ; *Apolipoproteins E/deficiency ; Cell Proliferation/drug effects ; Mice ; Neural Stem Cells/drug effects/metabolism ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Phosphorylation/drug effects ; },
abstract = {New cells are generated from neural stem cells (NSCs) in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus throughout life to shape brain function. Apolipoprotein E (ApoE) deficiency impairs hippocampal dentate gyrus development by affecting the neural progenitor pool over time. Impaired adult hippocampal neurogenesis has been reported in human ApoE4 and ApoE-knockout (ApoE[-/-]) mice. The ApoE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Our previous studies indicated that tanshinone IIA (tan IIA) has a broad range of pharmacological actions on AD. Here, we aimed to investigate the effects of 2 weeks of tan IIA (15 mg/kg, intraperitoneally, once daily) treatment on hippocampal neurogenesis in 1- and 3-month-old ApoE[-/-] mice. The results showed that tan IIA treatment significantly promoted cell proliferation and increased the density of immature neurons in the hippocampus. Mechanistically, tan IIA treatment elevated the levels of cyclic adenosine monophosphate (cAMP), cAMP/protein kinase A (PKA), and cAMP response element binding protein (CREB) phosphorylation, and subsequently increasing the production of brain-derived neurotrophic factor (BDNF). Furthermore, tan IIA is capable of promoting NSCs proliferation, differentiation, and survival in vitro. Collectively, the above findings indicated that tan IIA stimulates neurogenesis in the adult hippocampus of ApoE[-/-] mice possibly through the cAMP/PKA/CREB/BDNF signaling pathway. These results suggested that tan IIA may have neuroprotective effects against neurogenesis decline in ApoE[-/-] mice.},
}

Animals
*Neurogenesis/drug effects
*Brain-Derived Neurotrophic Factor/metabolism
*Hippocampus/drug effects/metabolism
*Signal Transduction/drug effects
*Cyclic AMP Response Element-Binding Protein/metabolism
*Cyclic AMP/metabolism
*Cyclic AMP-Dependent Protein Kinases/metabolism
*Abietanes/pharmacology
*Apolipoproteins E/deficiency
Cell Proliferation/drug effects
Mice
Neural Stem Cells/drug effects/metabolism
Mice, Knockout
Mice, Inbred C57BL
Male
Phosphorylation/drug effects

@article {pmid41273462,
year = {2025},
author = {Su, Y and Zhang, D and Li, Y and Gu, H and Li, W and Zhou, W and Zhao, N and Huang, X},
title = {Caenorhabditis Elegans Ortholog of TNF Alpha-Induced Protein 1 is Upregulated by TOL-1 and Exacerbates Amyloid-Beta-Associated Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {146},
pmid = {41273462},
issn = {1559-1182},
support = {KC-23236341//Yunnan University Graduate Research Innovation Fund/ ; No. 202403AC100007//Yunnan Fundamental Research Projects/ ; No. 32170184//Natural Science Foundation Program of China/ ; },
mesh = {*Caenorhabditis elegans/metabolism/genetics ; Animals ; *Amyloid beta-Peptides/metabolism/toxicity ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Up-Regulation ; Animals, Genetically Modified ; *Toll-Like Receptors/metabolism ; Humans ; Alzheimer Disease/pathology/metabolism ; },
abstract = {Neuroinflammation has been recognized as a central pathological mechanism in Alzheimer's disease (AD), modulated by diverse molecular pathways. Among these, the tumor necrosis factor superfamily (TNFSF) pathway serves as a pivotal mediator of inflammatory responses in higher organisms, representing a potential therapeutic target for AD treatment. Notably, TNF alpha-induced protein 1 (TNFAIP1) is significantly upregulated following amyloid-beta1-42 (Aβ1-42) accumulation in the postmortem brains of patients with AD and in transgenic Caenorhabditis elegans models. However, the regulatory mechanism of its ortholog F22E5.6 in C. elegans and its role in Aβ neurotoxicity remain elusive due to the absence of the core TNFSF members in this model. Through systematic screening of TNFSF orthologs, the trf-1 gene that encodes the adapter protein, TNF receptor-associated factor (TRAF), has been identified as a critical regulator in Aβ1-42-induced F22E5.6 overexpression of C. elegans. In this genetic model, the only Toll-like receptor TOL-1 in C. elegans serves as a potential receptor to activate TRF-1 and to transmit this signal to the SRC-2/PMK-3 axis, thereby executing the effects on mitochondrial homeostasis disequilibrium. These findings reveal the regulatory mechanism on Aβ1-42-induced F22E5.6/TNFAIP1 overexpression and its involvement in AD model of C. elegans, providing a clue to resolve the paradox of TNFSF-mediated inflammation in organisms lacking the canonical TNFSF pathway.},
}

*Caenorhabditis elegans/metabolism/genetics
Animals
*Amyloid beta-Peptides/metabolism/toxicity
*Caenorhabditis elegans Proteins/metabolism/genetics
*Up-Regulation
Animals, Genetically Modified
*Toll-Like Receptors/metabolism
Humans
Alzheimer Disease/pathology/metabolism

@article {pmid41272752,
year = {2025},
author = {Saraswathi, TS and Mothilal, M and Bukke, SPN and Thalluri, C and Chettupalli, AK},
title = {Recent advances in potential drug nanocarriers for CNS disorders: a review.},
journal = {Biomedical engineering online},
volume = {24},
number = {1},
pages = {137},
pmid = {41272752},
issn = {1475-925X},
mesh = {Humans ; *Central Nervous System Diseases/drug therapy ; *Drug Carriers/chemistry ; *Nanoparticles/chemistry ; Animals ; Blood-Brain Barrier/metabolism ; },
abstract = {BACKGROUND: Neurological disorders, including Parkinson's and Alzheimer's disease, impose a significant burden on individuals and healthcare systems. Effective treatment is often hindered by the restrictive nature of the blood-brain barrier (BBB), limiting drug access to the central nervous system (CNS).

AIM: The purpose of this review is to provide an overview of existing methods to deliver therapeutics to the CNS across the BBB with an emphasis on drug delivery systems that utilize nanotechnology.

METHOD/SOURCE: We performed a thorough review of the published literature on recently emerging trends in pharmacology and nanomedicine that have attempted to deliver drugs to the CNS by addressing the challenge of delivering therapeutics across the BBB.

RESULT/FINDING: Nanoparticles and nanocarriers have shown promise for crossing the blood-brain barrier (BBB), improving drug bioavailability in the brain, and facilitating targeted delivery. Several systems applying nanomaterials, including polymeric nanoparticles, liposomes, solid-lipid nanoparticles, and quantum dots, have successfully advanced through preclinical or early clinical studies. However, demonstrated evidence of the implementation and uptake of nanoparticles in specific antitumor and neurotherapeutic indications have several significant challenges, primarily due to safety, biocompatibility, and scalability.

CONCLUSION: The combination of traditional pharmacology and nanotechnology provides valuable opportunities for drug delivery to the CNS. Gains in the design of nanocarrier systems have great potential for addressing the limits of BBBs and for improving therapeutic outcomes in neurological disease, but more research is necessary for the development of translational clinical studies.},
}

Humans
*Central Nervous System Diseases/drug therapy
*Drug Carriers/chemistry
*Nanoparticles/chemistry
Animals
Blood-Brain Barrier/metabolism

@article {pmid41272481,
year = {2025},
author = {Li, Q and Degan, S and Galeffi, F and Colton, CA and Turner, DA},
title = {Dysregulated microvascular reactivity in hippocampus and cortex in CVN Alzheimer's disease mouse model.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X251383112},
doi = {10.1177/0271678X251383112},
pmid = {41272481},
issn = {1559-7016},
abstract = {Microvascular reactivity in acute cortical and hippocampal brain slices and hippocampal synaptic- evoked cerebral blood flow (CBF) in vivo were analyzed in a mouse model of Alzheimer's disease (AD, CVN). Microvessels underwent initial vasoconstriction (2 µM noradrenaline) then treatment with either 0.5 mM glutamate or 100 µM NMDA. In acute brain slices from young mice (<20 weeks) the glutamate and NMDA treatment led to dilation of capillaries in cortex and hippocampus, but not in aged CVN mice (>30 weeks, with AD pathology). Furthermore, 1 mM adenosine restored pre-constricted capillaries to control levels in WT but not in aged CVN brain slices. Stimulation of endothelial ET-1 receptors (10 nM ET-1) showed enhanced vasoconstriction in hippocampal capillaries of aged CVN slices, but blockade of both ET-1A/1B receptors did not alter basal capillary tone in aged CVN slices. Stimulation-evoked hippocampal CBF in vivo was significantly reduced in aged CVN mice. These results provide evidence for a progressive, complex age- and AD pathology-related impairment of vascular reactivity and vasodilation in the CVN model. The dysregulation of NVC function and reduced functional hyperemia in aged CVN AD mice may underscore dynamic hypoperfusion and metabolic insufficiency, which could accelerate progression in AD.},
}

@article {pmid41272422,
year = {2025},
author = {Wilson, RF and Harrison, DD and Amoakohene, E and Lyons, BH},
title = {Homicides among people with disabilities, United States, 2003-2022.},
journal = {Injury epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40621-025-00640-7},
pmid = {41272422},
issn = {2197-1714},
abstract = {BACKGROUND: People with disabilities (PwD) are at an increased risk of experiencing nonfatal violence; however, the risk of fatal violence victimization (i.e., homicide) among this population is less well established.

METHODS: We used National Violent Death Reporting System (NVDRS) data for homicide victims with disabilities for 2003 to 2022 in 50 states, the District of Columbia, and Puerto Rico. NVDRS is a surveillance system that collects data on violent deaths, linking information from death certificates, coroner or medical examiner records, and law enforcement reports. NVDRS does not currently include standard variables on disability status or disability type; these decedent characteristics were identified using a literal text search of textual data. Descriptive statistics were used to characterize homicides among PwD.

RESULTS: From 2003 to 2022, NVDRS collected 1,498 homicides among people with disabilities. The largest proportion of victims had a neurological disability (36.7%), followed by cognitive disability (35.5%), physical disability (22.4%), or unspecified disability type (5.4%); 18.2% had multiple disability types. Those aged ≥ 65 years accounted for 45.1% of all victims; the largest proportion of victims were ≥ 75 years old (29.7%). A firearm was used in 38.5% of these homicides. The top three precipitating circumstances of these homicides were: caregiver abuse and neglect (27.0%), argument (26.0%), and intimate partner violence (IPV; 24.0%). Caregiver abuse or neglect precipitated 38.1% of homicides among female victims, versus 19.1% of male victims. IPV precipitated 43.7% of female homicides, versus 9.1% of male homicides. Half (49.5%) of all victims had a mental health problem at the time of death; 23.3% had a history of ever being treated for a mental health problem; 17.8% were receiving mental health treatment at the time of death.

CONCLUSION: This study characterized homicides among PwD. Older adults accounted for nearly half of all victims, and mental health conditions such as dementia and Alzheimer's disease were frequently present among decedents, especially female victims. Among older adults and child victims, caregiver abuse/neglect was common. Our results underscore the importance of supporting caregivers of PwD, creating protective environments for PwD, systematically collecting data on violence against PwD, and tailoring prevention strategies to address the needs of PwD.},
}

@article {pmid41272400,
year = {2025},
author = {Shao, S and Lu, H and Zu, R and Chen, Y and Peng, Z and Peng, Q and Ma, H and Sun, Y},
title = {Pharmacological Regulation of Mitophagy by Natural Plant Products as a Therapeutic Target for Alzheimer's Disease.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70131},
pmid = {41272400},
issn = {1099-1573},
support = {CMC 2021//Horizontal research project of Chengdu Medical College/ ; 242102311258//Scientific and Technological Project of Henan Province/ ; 2021LHPG-08//Joint Fund of Chengdu Medical College and Chengdu Pidu District People's Hospital/ ; 231111312900//Henan Province key research and development project/ ; No. 2022M711080//Postdoctoral Foundation of China/ ; No. 32301030//The National Natural Science Foundation of China/ ; No. 82274612//The National Natural Science Foundation of China/ ; No. 82305087//The National Natural Science Foundation of China/ ; 2024KYCX003//Henan University of Chinese Medicine/ ; },
abstract = {Alzheimer's disease (AD), a prevalent senile dementia, is characterized by the progressive decline in cognitive function, accumulation of tau tangles and Aβ plaques. Despite significant research efforts in the field of AD, effective therapeutic drugs for its prevention and treatment remain elusive. Consequently, a more comprehensive understanding of the molecular mechanisms underlying the pathological processes of AD is crucial for novel therapeutic strategies. Mitophagy, the selective degradation of mitochondria through autophagy, is an essential mechanism for maintaining mitochondrial homeostasis in terms of both quantity and quality. Mitophagy plays a crucial role in numerous cellular processes, including inflammation, differentiation, and apoptosis. Recent studies have increasingly demonstrated that mitophagy is extensively characterized in AD and may represent a novel therapeutic strategy for its treatment. Notably, a number of natural plant products (NPPs) have been demonstrated to modulate mitophagy and intervene in the pathological process of AD. For instance, NPPs such as urolithin A and β-asarone have been reported to enhance mitophagy by activating the PINK1/Parkin pathway, thereby alleviating Aβ-induced neurotoxicity. The distinctive multi-target properties and favorable safety profiles of NPPs endow them with significant research potential and developmental value, establishing them as a vital resource for novel drug discovery. This review explores the mechanistic hypotheses linking mitophagy to AD pathology and provides a systematic overview of recent advances in representative NPPs that regulate mitophagy to alleviate AD-related impairments, offering new perspectives for the development of therapeutic strategies against AD.},
}

@article {pmid41272336,
year = {2025},
author = {Tang, C and Ding, Y and Yang, S and Lei, X and Zhang, M and Xu, B and He, D},
title = {Dual Mechanisms of Cognitive Function and Pathological Improvements by the Selective S1PR1/5 Modulator Siponimod in 3xTg-AD Mice.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {133},
pmid = {41272336},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology ; *Cognition/drug effects ; Microglia/drug effects/metabolism/pathology ; *Benzyl Compounds/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; *Azetidines/pharmacology/therapeutic use ; *Sphingosine-1-Phosphate Receptors/metabolism ; Disease Models, Animal ; Molecular Docking Simulation ; Signal Transduction/drug effects ; Male ; Cell Line ; Myelin Sheath/metabolism/drug effects ; *Sphingosine 1 Phosphate Receptor Modulators/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, with neuroinflammation and myelin dysfunction as crucial pathological mechanisms. Siponimod, a selective S1PR1/5 modulator, shows promising therapeutic potential through enhanced brain penetration and improved pharmacokinetic properties compared to first-generation modulators. Network pharmacology and molecular docking analyses were utilized to comprehensively elucidate the underlying mechanisms of Siponimod in the context of AD. Specifically, network pharmacology identified key targets and pathways associated with Siponimod, while molecular docking facilitated predictions of binding affinities to these targets. For in vitro assessments, BV2 microglia cells were used to investigate the effects of Siponimod after stimulation with LPS, focusing on inflammatory responses and cellular signaling pathways. Concurrently, in vivo studies employed the 3xTg-AD mouse model to investigate behavioral outcomes related to cognitive function, alongside evaluations of neuroinflammation and the integrity of myelin sheaths. Siponimod treatment resulted in a significant reduction in pro-inflammatory cytokines and ROS production in BV2 microglia cells, thereby indicating its robust anti-inflammatory and antioxidant properties. In the 3xTg-AD mouse model, administration of Siponimod led to marked improvements in cognitive performance as assessed through various behavioral tests. Additionally, there was a noteworthy decrease in Aβ plaque deposition, coupled with evidence of myelin repair, which was reflected in the increased expression of myelination-related proteins, namely OLIG2 and MBP. Furthermore, Siponimod was found to activate the PI3K-AKT signaling pathway, which plays a crucial role in promoting neuroprotection and enhancing cellular resilience against neurodegenerative processes. This study demonstrates that Siponimod effectively treats AD through dual mechanisms: reducing neuroinflammation and promoting myelin repair via the S1PR1/5 and PI3K-AKT signaling pathway. These findings suggest Siponimod's potential as a promising therapeutic agent for AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology
*Cognition/drug effects
Microglia/drug effects/metabolism/pathology
*Benzyl Compounds/pharmacology/therapeutic use
Mice
Mice, Transgenic
*Azetidines/pharmacology/therapeutic use
*Sphingosine-1-Phosphate Receptors/metabolism
Disease Models, Animal
Molecular Docking Simulation
Signal Transduction/drug effects
Male
Cell Line
Myelin Sheath/metabolism/drug effects
*Sphingosine 1 Phosphate Receptor Modulators/pharmacology/therapeutic use

@article {pmid41271757,
year = {2025},
author = {Rabiei, K and Petrella, JR and Lenhart, S and Liu, C and Hao, W and , },
title = {Data-driven modeling of amyloid-β targeted antibodies for Alzheimer's disease.},
journal = {NPJ systems biology and applications},
volume = {11},
number = {1},
pages = {134},
pmid = {41271757},
issn = {2056-7189},
support = {1R35GM146894/GM/NIGMS NIH HHS/United States ; 1R35GM146894/GM/NIGMS NIH HHS/United States ; DMS-2052676//National Science Foundation/ ; P30AG072958/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/immunology/chemistry/antagonists & inhibitors ; Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Kinetics ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta, which is strongly associated with disease progression and cognitive decline. Despite the approval of monoclonal antibodies targeting Aβ, optimizing treatment strategies while minimizing side effects remains a challenge. This study develops a mathematical framework to model Aβ aggregation dynamics, capturing the transition from monomers to higher-order aggregates, including protofibrils, toxic oligomers, and fibrils, using mass-action kinetics and coarse-grained modeling. Parameter estimation, sensitivity analysis, and data-driven calibration ensure model robustness. An optimal control framework is introduced to identify the optimal dose of the drug as a control function that reduces toxic oligomers and fibrils while minimizing adverse effects, such as amyloid-related imaging abnormalities (ARIA). The results indicate that Donanemab achieves the most significant reduction in fibrils. These findings provide a quantitative basis for optimizing AD treatments, providing valuable insight into the balance between therapeutic efficacy and safety.},
}

*Alzheimer Disease/drug therapy/metabolism
*Amyloid beta-Peptides/metabolism/immunology/chemistry/antagonists & inhibitors
Humans
*Antibodies, Monoclonal/therapeutic use/pharmacology
Kinetics

@article {pmid41271117,
year = {2025},
author = {Yin, C and Tang, X and Zeng, J and Wang, Z and Mi, J and Liang, Y and Qin, D and Feng, Q and Wu, A},
title = {Next-Generation Biosensor Technologies for Alzheimer's Disease: Innovations in Diagnosis, Monitoring, and Treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102954},
doi = {10.1016/j.arr.2025.102954},
pmid = {41271117},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, remains a global health crisis due to the lack of early diagnostic tools, dynamic monitoring strategies, and effective therapies. Current diagnostic methods such as cerebrospinal fluid (CSF) analysis and neuroimaging, while accurate, are invasive, expensive, and unsuitable for routine screening, highlighting the pressing need for alternative approaches. This review comprehensively examines the transformative role of next-generation biosensors in revolutionizing AD management. By leveraging breakthroughs in nanotechnology, materials science, and artificial intelligence (AI), modern biosensors enable ultrasensitive, non-invasive detection of AD biomarkers-including amyloid-β (Aβ), Tau proteins, and neurofilament light chain (NfL)-across diverse biofluids such as blood, saliva, and tears. We critically evaluate electrochemical, optical, and acoustic biosensing platforms, highlighting their integration into wearable and portable devices for real-time disease monitoring and personalized therapeutic interventions. Emerging trends such as AI-driven analytics, CRISPR-based diagnostics, and closed-loop neuromodulation systems are explored for their potential to decode disease progression and optimize treatment responses. Challenges in clinical translation, including sensor stability, regulatory hurdles, and ethical considerations, are addressed to pave the way for scalable, patient-centric solutions. By synthesizing cutting-edge advancements and interdisciplinary insights, this review charts a roadmap for biosensor technologies to shift AD care from reactive to proactive, ultimately improving quality of life for patients and caregivers.},
}

@article {pmid41270999,
year = {2025},
author = {Parveen, N and Qais, FA and Faheem, M},
title = {Molecular insights into diosgenin's role in preventing protein aggregation in neurodegenerative diseases.},
journal = {Biochimica et biophysica acta. Proteins and proteomics},
volume = {1874},
number = {1},
pages = {141116},
doi = {10.1016/j.bbapap.2025.141116},
pmid = {41270999},
issn = {1878-1454},
abstract = {Neurodegenerative disorders (ND) such as Parkinson's and Alzheimer's progressively impair the nervous system, leading to cognitive deterioration and motor dysfunction. A primary factor in these diseases is the accumulation of misfolded protein aggregates, which interfere with cellular processes and ultimately result in neuronal death. Preventing the formation of these toxic aggregates has the potential to protect neurons and slow the advancement of disease. This study examined the impact of diosgenin on protein aggregation, utilizing human serum albumin (HSA) as model protein. Diosgenin reduced ThT fluorescence by 64.35 % and decreased turbidity by 62.61 %, indicating a notable suppression of protein aggregation. The % α-helix in HSA experienced a decline from 57.68 % to 8.82 %, but diosgenin treatment restored it to 43.89 %. Binding studies demonstrated that diosgenin interacts with HSA with -11.0 kcal/mol binding energy, facilitated by van der Waals, hydrophobic and hydrogen bonding interactions, and stability of HSA-diosgenin complex was also validated using molecular simulations. To further elucidate the aggregation inhibition mechanism by diosgenin, advanced molecular dynamics simulations were employed. Diosgenin increased the solvent accessibility of the HSA282-292 oligomers, reduced β-sheet formation, and prevented H-bond interactions, key factors in aggregate formation. Molecular simulation of Aβ oligomers (Aβ16-22) also showed the diosgenin prevents oligomerization and β-sheet formation. We show that diosgenin presents a promising alternative due to its ability to stabilize protein structures and inhibit protein aggregation, making it a potential therapeutic candidate for NDs. However, further experimental validation in animal models is necessary to confirm diosgenin's anti-aggregation effects, particularly of amyloid-forming proteins.},
}

@article {pmid41270820,
year = {2025},
author = {Mayr, D and Preishuber-Pflügl, J and Koller, A and Migschitz, SM and Michael, J and Altendorfer, B and Rabl, R and Amschl, D and Hitzl, W and Aigner, L and Reitsamer, HA and Trost, A},
title = {The effect of CysLTR1 inhibition on cells of the retinal neurovascular unit in 5xFAD Alzheimer mice.},
journal = {Experimental eye research},
volume = {},
number = {},
pages = {110763},
doi = {10.1016/j.exer.2025.110763},
pmid = {41270820},
issn = {1096-0007},
abstract = {Alzheimer´s disease (AD) is a multifactorial neurodegenerative disease that affects both the brain and the retina. Many cerebral-associated AD pathologies, including neuroinflammation and vascular changes, have been reported to manifest in the retina. Furthermore, the neurovascular unit (NVU), composed of vascular cells, glia and neurons, regulates blood flow and neuronal metabolic activity and has been described to be dysfunctional in AD brains and retinas. As leukotrienes are modulators of both neuroinflammation and the vasculature, their receptors have been recognized as potential targets for ameliorating AD pathology. Therefore, the present study investigated the effects of the cysteinyl leukotriene receptor 1 (CysLTR1) antagonist montelukast (MTK) on retinal NVU cells in the 5xFAD mouse model of AD. Retinal analyses were performed in male and female 8-month-old 5xFAD mice and after 13-weeks of treatment with low and high doses of MTK or vehicle, and in age-matched controls. The retinal pericyte (PC) coverage was unchanged in AD, but CysLTR1 inhibition resulted in increased PC coverage in AD mice. Furthermore, an AD-associated decrease in capillary diameter was observed, which was not affected by CysLTR1 inhibition. The number of retinal microglial cells was increased in AD, independent of treatment. In addition, the astrocyte area and retinal ganglion cell density were not affected by either AD or CysLTR1 inhibition. In conclusion, the present study revealed minor AD-associated changes in retinal NVU cells in the 5xFAD mouse model. MTK treatment increased dose-independently PC coverage, but it remains to be clarified whether this affects the vessel tightness and blood flow.},
}

@article {pmid41270732,
year = {2025},
author = {Wang, JL and Sha, XY and Shao, Y and Zhang, ZH and Huang, SM and Lin, H and Gan, SY and Zhang, N and Xia, XY and Sun, YN and Ding, JH and Zhao, RQ and Cheng, J and Shang, P and Wang, JP and Liu, YJ and Yang, F and Xiao, P and Wang, LW and Zhao, DY and Tang, Y and Tie, L and Du, Y and Zhang, Y and He, JF and Sun, JP},
title = {Elucidating pathway-selective biased CCKBR agonism for Alzheimer's disease treatment.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2025.10.034},
pmid = {41270732},
issn = {1097-4172},
abstract = {Expressed in the entorhinal cortex (EC), the cholecystokinin (CCK) B receptor (CCKBR) plays an important role in memory and learning. Here, we identify that CCKBR-Gs and -Gq signaling, rather than CCKBR-Gi signaling, are beneficial for Alzheimer's disease (AD) treatment. Clinically, patients with more severe AD associated with lower CCKBR-Gq activity. The cryo-electron microscopy (cryo-EM) structures of CCKBR in complex with the endogenous agonist sulfated CCK8 (CCK8s) and 3 different G protein subtypes revealed that distinct receptor conformations contribute to selective G protein bias. Leveraging these structural insights, we rationally develop synthetic CCKBR agonists, including a Gi-biased agonist (z-44) and a Gq-biased agonist (3r1). Notably, 3r1 demonstrates therapeutic potential by ameliorating cognitive decline in 5×FAD mice, reducing the number of amyloid-β plaques, and promoting long-term potentiation (LTP) via upregulation of the α-secretase (ADAM10) and the calcium signaling molecule PLCB4. Our findings suggest that synthetic biased agonists targeting CCKBR-Gq signaling have therapeutic potential for AD.},
}

@article {pmid41270541,
year = {2025},
author = {Zhang, M and Liu, X and Ren, Y and Li, L and Wang, R and Sun, L and Ma, Q},
title = {Decoding alzheimer's: The role of EEG rhythms and aperiodic components in cognitive decline.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {181},
number = {},
pages = {2111437},
doi = {10.1016/j.clinph.2025.2111437},
pmid = {41270541},
issn = {1872-8952},
abstract = {OBJECTIVE: To investigate detailed alterations in brain electrical activity and their relationship with cognitive decline in Alzheimer's disease (AD) using electroencephalogram (EEG) power spectrum analysis.

METHODS: EEG data from 80 AD patients and 80 healthy control (HC) were analyzed, focusing on theta and alpha band powers, aperiodic offset, and exponent. Topographic and gender-specific analyses were conducted to explore associations with disease progression and cognitive impairment.

RESULTS: AD patients showed increased theta and alpha band powers, with theta band power exhibiting statistically significant differences. Globally elevated theta band power correlated with cognitive impairment severity. Higher aperiodic offsets and exponents were observed in AD patients, exhibiting upward trends with disease progression. Male AD patients displayed more pronounced EEG abnormalities and unique Montreal Cognitive Assessment (MOCA) score patterns.

CONCLUSIONS: Our findings highlight the critical role of theta band power in AD pathology and suggest potential EEG biomarkers for neurodegenerative changes. Gender-specific differences emphasize the importance of personalized approaches in AD diagnosis and treatment.

SIGNIFICANCE: This study provides novel neurophysiological insights into AD, underscoring the clinical utility of EEG markers and the necessity for gender-specific considerations in precision medicine for AD.},
}

@article {pmid41269690,
year = {2025},
author = {Brickman, AM and Muller, C and Warren, JR and Grodsky, E and Kim, S and Culbertson, MJ and Thyagarajan, B and Manly, JJ},
title = {Alzheimer Disease Blood Biomarker Concentrations Across Race and Ethnicity Groups in Middle-Aged Adults.},
journal = {JAMA network open},
volume = {8},
number = {11},
pages = {e2545046},
doi = {10.1001/jamanetworkopen.2025.45046},
pmid = {41269690},
issn = {2574-3805},
mesh = {Humans ; Biomarkers/blood ; Female ; Male ; *Alzheimer Disease/blood/ethnology ; Middle Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Cohort Studies ; Neurofilament Proteins/blood ; Hispanic or Latino/statistics & numerical data ; United States/epidemiology ; Glial Fibrillary Acidic Protein/blood ; *Ethnicity/statistics & numerical data ; Black or African American/statistics & numerical data ; White People/statistics & numerical data ; White ; },
abstract = {IMPORTANCE: The incidence and prevalence of clinical Alzheimer disease (AD) are higher among Black and Latinx older adults than among White older adults. Past studies that compared plasma AD biomarker concentrations among groups minoritized by their race and ethnicity yielded inconsistent findings; however, these efforts did not include population representative samples or statistical procedures to ensure population representation.

OBJECTIVE: To examine race and ethnicity differences in plasma AD biomarker concentrations and in the association between biomarkers and medical conditions in a US population-representative cohort of middle-aged adults (approximately 58 years of age).

Data for this cohort study came from the High School and Beyond sample, a nationally representative cohort of high school sophomores and seniors who were recruited in 1980. In 2021, a subset of participants provided blood samples that were assayed for amyloid-β (Aβ42/Aβ40 ratio), phosphorylated tau-181 (pTau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). The analyses for the present study were conducted between July 2, 2024, and August 26, 2025, using data collected during the 2021 follow-up study.

EXPOSURES: Race and ethnicity groups and common medical conditions.

MAIN OUTCOMES AND MEASURES: General linear models with Wald tests were used to compare biomarker concentrations between race and ethnicity groups and to test interactions with common medical conditions using unadjusted biomarker values and models adjusted to ensure population representation with inverse probability weighting and multiple imputation.

RESULTS: The sample included 4340 adults (mean [SD; range] age, 58.1 [1.1; 56-63] years; 2400 [55.3%] women); 630 (14.4%) were Black, 900 (20.7%) were Latinx, and 2610 (60.1%) were White. Black participants had a lower Aβ42/Aβ40 ratio (d = -0.002; 95% CI, -0.004 to -0.000; P = .04) and lower NfL concentrations (d = -1.16; 95% CI, -2.15 to -0.16; P = .02) than White participants, but these differences were attenuated when models were adjusted for population representation (d = 0.000; 95% CI, -0.002 to 0.002; P = .85 for Aβ ratio; d = -0.88; 95% CI, -1.78 to 0.02; P = .05 for NfL). Latinx participants had lower GFAP concentrations than White participants (d = -3.87; 95% CI, -7.30 to -0.45; P = .03), but these differences were also attenuated when models were adjusted for population representation (d = 3.36; 95% CI, -3.13 to 9.86; P = .31). In general, estimated biomarker means were similar between race and ethnicity groups. History of type 2 diabetes was associated with increased NfL concentration (d = 0.19; 95% CI, 0.07 to 0.30; P = .04), and high body mass index was associated with lower Aβ42/Aβ40 ratio (d = -0.13; 95% CI, -0.21 to -0.06; P = .02); whereas high cholesterol was associated with lower pTau-181 concentration (d = -0.18; 95% CI, -0.25 to -0.10; P = .01) and high BMI was associated with lower GFAP concentration (d = -0.30; 95% CI -0.44 to -0.16; P = .01). No differences in associations between morbidities and AD biomarker concentrations were detected across race and ethnicity groups.

CONCLUSIONS AND RELEVANCE: In this cohort of middle-aged adults, the use of appropriate statistical estimation to ensure population representation indicated that blood-based AD biomarker concentrations were not distinguishable among race and ethnicity groups. Common medical conditions were associated with plasma biomarker concentrations similarly across race and ethnicity groups. These results highlight the importance of considering population representation and comorbid conditions in AD research to ensure accurate characterization of disease pathophysiology and improve precision of diagnostic and treatment strategies for populations that experience AD disparities.},
}

Humans
Biomarkers/blood
Female
Male
*Alzheimer Disease/blood/ethnology
Middle Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Cohort Studies
Neurofilament Proteins/blood
Hispanic or Latino/statistics & numerical data
United States/epidemiology
Glial Fibrillary Acidic Protein/blood
*Ethnicity/statistics & numerical data
Black or African American/statistics & numerical data
White People/statistics & numerical data
White

@article {pmid41269403,
year = {2025},
author = {Jin, J and Hand, R and Meltzer, M and Abate, C and Geva, M and Hayden, MR and Ross, CA},
title = {Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {121},
pmid = {41269403},
issn = {1559-1182},
mesh = {*Receptors, sigma/antagonists & inhibitors/agonists/metabolism ; *Huntington Disease/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Sigma-1 Receptor ; *Piperidines/pharmacology/therapeutic use ; Mice ; Humans ; Neurons/drug effects/metabolism/pathology ; Huntingtin Protein/metabolism ; },
abstract = {Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer's Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.},
}

*Receptors, sigma/antagonists & inhibitors/agonists/metabolism
*Huntington Disease/drug therapy/pathology/metabolism
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
Sigma-1 Receptor
*Piperidines/pharmacology/therapeutic use
Mice
Humans
Neurons/drug effects/metabolism/pathology
Huntingtin Protein/metabolism

@article {pmid41268794,
year = {2025},
author = {Zhang, H and Ya, J and Liao, X and Du, X and Zhao, C and Ren, J and Qu, X},
title = {In Situ Activatable Hydrogen-Bonded Organic Framework-Based Nanozyme as NADH Peroxidase Mimic Restoring Homeostasis for Treatment of Alzheimer's Disease.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e09547},
doi = {10.1002/smll.202509547},
pmid = {41268794},
issn = {1613-6829},
support = {2022YFA1205804//National Key R&D Program of China/ ; T249526//National Natural Science Foundation of China/ ; 22437006//National Natural Science Foundation of China/ ; 22237006//National Natural Science Foundation of China/ ; },
abstract = {Nicotinamide adenine dinucleotide (NAD) serves as a vital regulator in metabolic networks, and the decrease in the level of its oxidized form, NAD+, is closely related to Alzheimer's disease (AD). However, unsatisfactory efficacy, non-targeted and imprecise treatment, along with interconnected pathogenic factors in AD, constrain the therapeutic efficacy of current AD therapeutic strategies. Herein, in lieu of complex multi-module treatments for pathogenesis, a bespoke in situ activatable hydrogen-bonded organic framework (HOF)-based nanozyme (denoted as NADH@Pre-Cu-HOF@KD8) has been constructed to modulate multiple interconnected homeostatic imbalances in AD. Benefiting from the specific organic monomers, 2,2'-bipyridine-5,5'-dicarboxylic acid, NADH@Pre-Cu-HOF@KD8 can sequester neurotoxic Cu[2+] from amyloid-β (Aβ)-Cu[2+] by competitive binding. The segregation of Cu[2+] from Aβ mitigated the generation of reactive oxygen species, Aβ toxicity, and alleviated the activation of microglia cells. Moreover, HOF-based nanozyme possessed NADH peroxidase (NPX)-like catalytic activity after binding Cu[2+], which can reduce oxidative stress and elevate compromised NAD+ levels, thereby restoring mitochondrial impairment and adenosine triphosphate (ATP) production. Spatiotemporally precise intervention is enabled through targeted delivery mediated by peptide modification and lesion-specific activation. Notably, cognitive deficits, neuropathology, and homeostatic markers in a 3xTg-AD mouse model are ameliorated upon treatment. By employing a facile HOF platform to modulate multiple interconnected pathological homeostatic imbalances in AD-copper toxicity, NAD[+] depletion, oxidative stress, and Aβ toxicity-this strategy offers a paradigm for ameliorating AD-associated homeostatic imbalances.},
}

@article {pmid41268790,
year = {2025},
author = {Coburn, MA and Eskandari-Sedighi, G and Hasselmann, J and England, W and Shabestari, SK and Mansour, K and McQuade, A and Mgerian, MA and Chadarevian, JP and Tu, C and Silva, J and Beck, J and Keulen, Z and Spitale, RC and Davtyan, H and Blurton-Jones, M},
title = {Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70930},
doi = {10.1002/alz.70930},
pmid = {41268790},
issn = {1552-5279},
support = {//Cure Alzheimer's Fund/ ; Discovery23-10//Alzheimer Society of Canada/ ; //The Larry L. Hillblom Foundation : 2024-A-023-FEL and 2025-A-175-FEL/ ; A2025007F//BrightFocus Postdoctoral Fellowship Program in Alzheimer's/ ; P30CA-062203//NIH / ; 1S10RR025496-01//NIH / ; 1S10OD010794-01//NIH / ; 1S10OD021718-01//NIH / ; 2024-A-023-FEL//NIH / ; NS082174//NIH Training Grant/ ; AG000096//NIH Training Grant/ ; //Susan Scott Foundation/ ; ADSF-21-829655-C/ALZ/Alzheimer's Association/United States ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism ; Animals ; Humans ; Mice ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Mice, Transgenic ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {INTRODUCTION: Recent studies have identified important species-dependent differences in the response of microglia to β-amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer's disease (AD) remains unclear.

METHODS: We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell-derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling.

RESULTS: The combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct "rod" morphology in human microglia. The rod morphology could be induced with type-I interferon treatment in vitro.

DISCUSSION: We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.

HIGHLIGHTS: Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD. Combined Alzheimer's disease pathologies lead to an expansion of disease-associated microglia (DAM) and exacerbate Interferon-responsive and cytokine/chemokine-enriched states in xenotransplanted human microglia. The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration. Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) -microglia with type-I interferons.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/pathology/metabolism
Animals
Humans
Mice
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*tau Proteins/metabolism
Plaque, Amyloid/pathology/metabolism
Mice, Transgenic
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41268620,
year = {2025},
author = {Sun, L and Wang, J and Zhang, L},
title = {The Role of Sphingomyelin Synthase 2 in Lipid Metabolism and Its Implications in Diseases.},
journal = {Cell biology international},
volume = {},
number = {},
pages = {},
doi = {10.1002/cbin.70103},
pmid = {41268620},
issn = {1095-8355},
support = {//This study was supported by National Natural Science Foundation of China (82272306), Taishan Scholars Program (tstp20221142), and Joint Innovation Team for Clinical & Basic Research [202409]./ ; },
abstract = {Sphingomyelin synthase 2 (SMS2) is a crucial enzyme predominantly localized to the plasma membrane, playing an essential role in sphingomyelin metabolism and signaling. SMS2 catalyzes the final step in the biosynthesis of sphingomyelin by transferring phosphocholine from phosphatidylcholine to ceramide, resulting in the production of sphingomyelin and diacylglycerol. This enzymatic activity dynamically regulates the intracellular levels of ceramide, diacylglycerol, and phosphatidylcholine, thereby influencing several critical cellular processes. SMS2 is integral to multiple signaling pathways, including TGF-β/Smad, NF-κB, and CXCL12/CXCR4, which are involved in cancer progression and platelet activation. SMS2 displays versatile enzymatic activities, including phospholipase C activity and ceramide phosphoethanolamine synthesis. Dysregulation of SMS2 is associated with various pathological conditions, such as skin barrier dysfunction, skeletal disorders, inflammatory diseases, and different types of cancer. Targeting SMS2 through inhibition or modulation demonstrates therapeutic potential in treating multiple conditions, including pancreatic cancer, Alzheimer's disease, and atherosclerosis, by impacting tumor growth dynamics and cellular migration. Given its multifaceted role in diverse pathological processes and its promise as a therapeutic target, further research on SMS2 is essential for the development of innovative treatment strategies aimed at cancer therapy, inflammation regulation, and overcoming drug resistance.},
}

@article {pmid41268264,
year = {2025},
author = {Chen, J and Zhao, J and Fan, Y and Jin, Y and Mi, R and Wang, H and Yu, S and Feng, X and Zhang, Y and Ren, G},
title = {Predictive value of beta amyloid, phosphorylated Tau, neurofilament light chain, and glial fibrillary acidic protein for depression in Alzheimer's disease.},
journal = {American journal of translational research},
volume = {17},
number = {10},
pages = {7789-7802},
pmid = {41268264},
issn = {1943-8141},
abstract = {OBJECTIVES: To investigate differences in biochemical markers and their association with depressive symptoms in patients with Alzheimer's disease (AD) with and without concurrent depression.

METHODS: In this retrospective case-control study, 329 AD patients admitted to Beijing Panjiayuan TCM-Western Integrated Hospital between May 2019 and May 2022 were included. Patients were categorized into a comorbid depression group (n=167) and a non-depression group (n=162) based on Cornell Scale for Depression in Dementia (CSDD) scores. Biochemical markers, including β-amyloid proteins (Aβ1-42, Aβ1-40), phosphorylated Tau proteins (p-Tau181, p-Tau217), neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and inflammatory cytokines, were measured and statistically analyzed.

RESULTS: High-density lipoprotein cholesterol (HDL-C) was significantly lower in the comorbid depression group (P<0.001). Levels of Aβ1-42 (P=0.012), Aβ1-40 (P=0.006), p-Tau181 (P=0.003), p-Tau217 (P=0.003), NfL (P<0.001), and GFAP (P=0.008) were significantly elevated in the depression group compared to the non-depression group. Additionally, interleukin-10 (P=0.004) and interleukin-6 (P=0.047) levels were higher, while interleukin-1β (P<0.001) was lower in the comorbid depression group. Receiver operating characteristic curve identified HDL-C (area under the curve [AUC]=0.602), p-Tau217 (AUC=0.595), NfL (AUC=0.692), GFAP (AUC=0.580), and IL-1β (AUC=0.600) as significant predictors of depression severity.

CONCLUSIONS: Specific biochemical markers, including HDL-C, Aβ42/40, p-Tau217, NfL, GFAP, and IL-1β, are independently associated with depression in AD patients. A combined biomarker model may improve prediction of comorbid depression in AD and provide guidance for personalized treatment.},
}

@article {pmid41268048,
year = {2025},
author = {Moczygemba, W and Bradley, D and Carmona, R and Celano, V and Farley, L and Valverde, S and Sampley, A and Stratton, L},
title = {Perspectives on meaningful dementia treatment and care from those with lived experience.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70175},
doi = {10.1002/trc2.70175},
pmid = {41268048},
issn = {2352-8737},
abstract = {UNLABELLED: The ongoing conversations surrounding the importance of minimal clinically important differences and descriptions of meaningful impacts must include the voices of those living with Alzheimer's disease and related dementias. To provide this perspective, members of the Alzheimer's Association Early Stage Advisory Group were asked to describe what matters most to them, their experiences with treatment, how they define meaningful care, and what would provide them with feelings of progress and hope. Responses offer differing yet complementary definitions of a quality life, ways in which clinicians and providers can recognize and support the person behind the diagnosis, and how participating in clinical trials can bring hope - both now and for the future. By centering on the lived experiences and perspectives of those people living with dementia, this article provides insight for those seeking to develop novel treatments and provide care and support, both now and in the future.

HIGHLIGHTS: Maintaining independence, purposeful living, and social connection are among what matter most to those living with dementia.Meaningful treatment and care are person-centered and responsive to the needs and wants of the person living with dementia.Participating in clinical trials can have meaningful physical, cognitive, and psychosocial impacts for those living with dementia.},
}

@article {pmid41267904,
year = {2025},
author = {Zhao, F and Li, Y and Yi, C and Li, X and Huang, G and Chen, X and Li, Y and Zhang, J},
title = {Global, regional, and national burdens of early-onset Alzheimer's disease and other dementias in women, 1990 to 2021.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395223},
pmid = {41267904},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease and other dementias disproportionally impacts women. Novel treatment makes understanding of early-onset cases unprecedentedly important.

OBJECTIVE: We aimed to examine Alzheimer's disease and other dementias incidence, DALYs, trends, and risk factors among women aged under 65 years from 1990 to 2021.

METHODS: Using Global Burden of Diseases Study, we estimated the trend of Alzheimer's diseases and other dementias age-standardized incidence and disability-adjusted life-years (DALYs) among women aged under 65 years by social development index (SDI) worldwide during 1990 to 2021.

RESULTS: Globally, in 2021 there were 4.3 million prevalent cases among middle-aged women, with the incident cases doubled from 0.4 million to 0.8 million during 1990-2021. The largest increases in incidence and DALYs were found in high-middle SDI countries (0.27%/year) and low-middle SDI countries (0.19%/year), respectively. The incidence rate doubled once with every five years of age increase. The two contributors, which were high body mass index and high fasting plasma glucose, rapidly grew from 1990 to 2021.

CONCLUSIONS: The substantial increase of early-onset Alzheimer's disease and other dementias among middle-aged women requires attention, especially targeted at the increasing reversible lifestyle risk factors.},
}

@article {pmid41267515,
year = {2025},
author = {Ünal, D and Sarıköse Özgüven, A},
title = {Exosomes: New Biomarker and Therapeutic Candidates in Autism Spectrum Disorder Research.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-47},
doi = {10.1017/neu.2025.10047},
pmid = {41267515},
issn = {1601-5215},
abstract = {BACKGROUND: There is no recognized cure or specific biomarker for autism spectrum disorder (ASD). Exosomes are small vesicles that carry proteins, lipids, and nucleic acids. They have been investigated for diseases such as Parkinson's and Alzheimer's. As the conclusions were on the biological utility of exosomes as a non-invasive brain biopsy, some animal, human, and in vitro exosome studies have also been presented in the ASD field. The purpose of this review is to compile the studies that have established a relationship between ASD and exosomes so far and discuss their potential for linking the gap between the laboratory and clinic.

METHODS: In this systematic review, 31 PubMed articles were identified using the keywords "exosomal," "exosome," and "autism spectrum disorder." After excluding 16 reviews, 4 irrelevant studies, and 1 preprint, and adding 5 relevant articles, 15 research articles were included based on PRISMA criteria. The articles were investigated and reviewed by both authors. Their methodology and results are also discussed according to two main streams in studies.

RESULTS: Numerous studies have identified potential biomarkers, including mitochondrial DNA (mtDNA7S), cytokines including IL-1β, TNF-α, and IL-6, and different types of RNAs by comparing the exosomal contents of ASD patients or models with controls. In studies that focused on treatment, behavioral improvements were shown in ASD model mice.

CONCLUSION: Since there are presently no reliable biomarkers or effective treatments for ASD, exosome-based research offers a promising avenue for early diagnosis and the creation of tailored therapies.},
}

@article {pmid41265552,
year = {2025},
author = {Sardari, M and Sahafi, OH and Rezayof, A},
title = {Mitochondria serve as indispensable components of neuron-glia crosstalk in the trajectory of Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {150040},
doi = {10.1016/j.brainres.2025.150040},
pmid = {41265552},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a multiplex and progressive neurodegenerative disorder commonly recognized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and dysfunction in the cholinergic and glutamatergic systems. At the early stages of AD, mitochondrion operates as a neuroprotective organelle in both neuronal and glial cells by compensating energy fluctuations. As the disease progresses, mitochondrial function in both neurons and glial cells deteriorates, culminating in impaired cellular metabolism and glial hyperactivation. This time-dependent hyperactivation of microglia and astrocytes sequentially promotes the release of pro-inflammatory cytokines, elevates reactive oxygen species, disrupts calcium homeostasis, and increases oxidative stress. Altogether, these processes drive neuroinflammation, which both influences and is influenced by mitochondrial activity. Additionally, mitochondrial dysfunction across the disease trajectory hampers communication between neurons and glial cells, promoting excitotoxicity in neurons. This review emphasizes the vital role of mitochondrial dynamics in AD pathophysiology across different stages and explores how cell-specific targeting of mitochondrial activity could mitigate neuroinflammation, restore neuronal function, and offer potential treatment benefits. Enhancing mitochondrial function in healthy neurons and glial cells, particularly in microglia as a compensatory mechanism, especially at the early stage of the disease or restoring mitochondrial function of surviving neurons at the later stages, may promote neuroprotection and improve neuron-glia interactions, thus offering a potential strategy for AD treatment.},
}

@article {pmid41265341,
year = {2025},
author = {Yuan, X and Gao, L and Peng, Y and She, T and Wang, J},
title = {A deep representation learning algorithm on drug-target interaction to screen novel drug candidates for Alzheimer's disease.},
journal = {Artificial intelligence in medicine},
volume = {171},
number = {},
pages = {103301},
doi = {10.1016/j.artmed.2025.103301},
pmid = {41265341},
issn = {1873-2860},
abstract = {Alzheimer's disease (AD) is a serious neurodegenerative brain disorder with complex pathophysiology. While currently available drugs can provide symptomatic benefits, they often fail to cure the disease. Thus, there is an urgent need to explore new therapeutic agents. In this study, we developed DTIP (Drug-Target Interaction Prediction), a machine learning-based approach to search novel drugs for AD by utilizing the information of drug-target interaction (DTI). By training a Skip-gram model on drug-target sequences derived from known DTI information, the algorithm learned the drug-target relationship embeddings and to predict potential drug candidates for diseases like AD. For AD, we compiled 917 risk genes and identified 292 potential drugs via the new algorithm. We further performed molecular docking by AutoDock Vina and conducted Inverted Gene Set Enrichment Analysis (IGSEA) on these drug candidates. Our results identified that several drugs could be promising for AD treatment, including human C1-esterase inhibitor, quetiapine, dasatinib, miconazole, aniracetam, chlorpromazine, hypericin, entrectinib, torcetrapib, bosutinib, sunitinib, aniracetam, rosiglitazone, tarenflurbil, milrinone, and MITO-4509. Results from this study also provided insights for understanding the molecular mechanisms underlying AD. As a systematic and versatile method, our approach can also be applied to identify efficacious therapies for other complex diseases.},
}

@article {pmid41265212,
year = {2025},
author = {Patel, Y and Sharma, P and Kumar, A and Parmar, HS and Inwati, GK},
title = {Design, Ssynthesis, and biological evaluation of β-secretase inhibitors: An integrated study of molecular docking, dynamics, pharmacokinetics, quantum chemistry, and in-vitro analysis for Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {167},
number = {},
pages = {109267},
doi = {10.1016/j.bioorg.2025.109267},
pmid = {41265212},
issn = {1090-2120},
abstract = {Present paper elicits the synthesis of a series of 2,2-dimethyl-2H-[1,3]dioxino[4,5-b]pyrrol-4(7H)-one derivatives as novel selective BACE1 inhibitors for the treatment of Alzheimer's disease (AD). A four-component, solvent-free condensation process, catalyzed by 10 mol% NiCl2·6H2O strategy was explored to achieve their synthesis. The structures of the synthesized compounds were ascertained using different spectroscopic techniques, including FT-IR, [1]H NMR, [13]C NMR, mass spectrometry, and elemental analysis. In silico molecular docking and molecular dynamics simulations suggest that these compounds exhibit strong potential as β-secretase (BACE1) inhibitors, demonstrating high interaction and binding energies compared to reference inhibitors AZD3293 and E2602. Notably, compounds 5p displayed significant inhibitory interactions, effectively suppressing the catalytic dyad (Asp A:228 and Asp A:32) of BACE1. To further validate the computational findings, in vitro BACE1 enzymatic inhibition assays were performed on the most interactive molecule 5p. Additionally, ADMET descriptors and density functional theory (DFT) calculations were employed to assess the pharmacokinetics, chemical stability, and binding affinity of the synthesized compounds. The findings from this study pave the way for future in vivo investigations to assess the reversal of Alzheimer's disease phenotypes, along with comprehensive safety and toxicity evaluations.},
}

@article {pmid41264165,
year = {2025},
author = {Gao, H and Cheng, F and Zhang, Z and Yan, B and Liao, P and Zhang, S and Li, D and Chen, F and Lei, P},
title = {Breaking the Alzheimer's Treatment Stalemate: Synergistic Application Strategies of Nanomaterials and Pharmaceutical Agents.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {107},
pmid = {41264165},
issn = {1559-1182},
support = {grant no. 82271401//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/diagnosis ; Humans ; *Nanostructures/therapeutic use ; Animals ; Drug Delivery Systems/methods ; Nanomedicine/methods ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid beta accumulation and tau pathology propagation. Nanomedicine, a discipline enabling targeted drug delivery with precision, holds significant promise in the treatment of neurodegenerative diseases. This review explores the diagnostic and therapeutic applications of nanomaterials in neurodegenerative diseases, particularly AD, emphasizing their properties and their role in modulating pathogenic proteins. Advances in the development of novel anti-AD nanomedicines and their clinical progress are also highlighted. Despite the growing potential of nanotechnology in AD therapy, a definitive cure remains elusive. The review further addresses the current challenges in the field of AD nanomedicines and outlines future research directions to propel their development.},
}

*Alzheimer Disease/drug therapy/diagnosis
Humans
*Nanostructures/therapeutic use
Animals
Drug Delivery Systems/methods
Nanomedicine/methods

@article {pmid41262573,
year = {2025},
author = {Demsey, LL and Burch, D and Lin, E and Quach, D and Podvin, S and Boyarko, B and Levey, AI and Weinshenker, D and Edland, S and Galasko, D and Jacobs, H and Bang, A and Neil, A and Silverman, J and Feldman, HH and Hook, V},
title = {Atomoxetine Drug Properties for Repurposing as a Candidate Alzheimer's Disease Therapeutic Agent.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {11},
pages = {3757-3772},
pmid = {41262573},
issn = {2575-9108},
abstract = {Ongoing Alzheimer's disease (AD) drug development research addresses the need for therapeutic agents that can ameliorate cognitive symptoms and attenuate the course of AD synaptic deficits and neurodegeneration. There is growing interest in evaluating FDA-approved drugs for repurposing as candidate AD therapeutics. Such drugs have the advantage that data are available about their pharmaceutical properties, including doses, pharmacokinetics, pharmacodynamics, biomarkers, metabolism, and safety, to inform the design of clinical drug trials. Importantly, the suitability of such drugs with properties needed for AD requires evaluation. In the early stage of AD, degeneration of the locus coeruleus (LC) brain region results in the reduction of noradrenergic neurons and the loss of the neurotransmitter norepinephrine (NE) that regulates cognition and degeneration. Elevation of extracellular NE through inhibition of the NE transporter (NET) is hypothesized to ameliorate AD deficits. Notably, the NET reuptake inhibitor atomoxetine, an FDA-approved drug for the treatment of attention deficit hyperactivity disorder (ADHD), provides an attractive candidate as an AD therapeutic agent because it may attenuate cognitive decline in AD patients, positively impact AD biomarkers, and reduce neuropathology. The goal of this review is to assess atomoxetine for repurposing in AD based on its ability to improve cognition, regulate NE, impact AD biomarkers, and preserve LC neuronal function, with suitable pharmacokinetics, drug metabolism, and safety based on analysis of clinical and preclinical studies. Evidence for neuroprotective effects of atomoxetine in the early stage of AD at clinically safe doses with suitable pharmaceutical properties supports its candidacy as a repurposed drug for AD therapeutics.},
}

@article {pmid41262391,
year = {2025},
author = {Latella, D and Calderone, A and Casella, C and De Luca, R and Gangemi, A and Impellizzeri, F and Caliri, S and Quartarone, A and Calabrò, RS},
title = {Cognitive behavioral therapy for insomnia in neurodegenerative disorders-targeting sleep disturbances in Alzheimer's and Parkinson's disease: a scoping review.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1700496},
pmid = {41262391},
issn = {1664-1078},
abstract = {INTRODUCTION: Insomnia is highly prevalent in neurodegenerative disorders, yet pharmacological options carry safety and tolerability concerns. This scoping review mapped contemporary evidence for cognitive behavioral therapy for insomnia (CBT-I) across Alzheimer's disease (AD), mild cognitive impairment (MCI), and Parkinson's disease (PD).

METHODS: Following a preregistered protocol (OSF DOI: 10.17605/OSF.IO/8VP3F), we searched PubMed, Cochrane Library, Web of Science, and Scopus for studies published 2015-2025. We screened English-language studies in adults and applied dual independent review with consensus resolution. Of 105 records, 70 were screened after de-duplication, and 8 met eligibility criteria.

RESULTS: Across randomized trials, pilot and feasibility studies, and single-case experimental designs, CBT-I-delivered in person or via telehealth-consistently reduced insomnia severity and improved sleep quality, with frequent ancillary gains in mood, anxiety, and daytime functioning. Remote and digitally augmented delivery appeared feasible and acceptable for cognitively vulnerable adults and caregivers. Early signals suggested potential cognitive benefits in prodromal populations (AD/MCI), and exploratory observations linked improved sleep with plausible neurobiological mechanisms such as amyloid-beta dynamics. In PD, findings aligned with a mechanistic pathway in which presleep cognitive arousal, safety behaviors, and dysfunctional sleep beliefs are modifiable targets. Non-pharmacological comparators (e.g., mindfulness, therapeutic exercise, neuromodulation) also showed benefits, helping contextualize where CBT-I may offer disorder-relevant leverage on insomnia outcomes.

DISCUSSION: The overall strength of evidence is tempered by small samples, heterogeneity in comparators and dosing, short follow-up, and inconsistent reporting of clinically meaningful change. Priorities include multicenter randomized trials with standardized sleep and cognitive endpoints, longer observation, head-to-head comparative effectiveness with economic evaluation, adaptive protocols tailored to PD-specific disruptors, and mechanistic studies integrating digital phenotyping and biomarkers to test durability and downstream clinical impact.},
}

@article {pmid41262225,
year = {2025},
author = {Bayram, E},
title = {Sex and gender differences in Lewy body dementia: a narrative review.},
journal = {Equity neuroscience},
volume = {1},
number = {2},
pages = {},
pmid = {41262225},
issn = {3050-8401},
abstract = {Lewy body dementia (LBD), including Parkinson's disease dementia and dementia with Lewy bodies, is one of the most prevalent and burdensome type of dementias. Clinical diagnostic accuracy during life remains limited and there are currently only symptomatic therapy options without disease modification. However, recent advances in biomarkers and clinical trials are promising. Literature so far showed sex and gender differences in older adults without cognitive changes, people with all-cause dementia, Alzheimer's disease, and Parkinson's disease. While the number of studies in LBD are lower, understanding sex and gender differences and the underlying reasons can improve both diagnosis and treatment for LBD. Accordingly, the aim of this narrative review is to provide a summary of the literature for sex and gender differences in LBD. Majority of the studies for LBD investigating sex/gender differences so far focused on sex, with sex and gender terms being misused at times. Experiences of people in non-binary categories for sex or gender have yet to be investigated. While more research is needed, findings so far outline sex differences in prevalence, risk factors, biomarkers, symptoms, progression, treatment, daily life, and pathology for LBD. Sex-specific risk factors have also been reported, emphasizing the value of sex-stratified analyses and investigating female/male-specific factors such as sex hormones, menopause, and sex chromosomes. Lack of adequate research representation for females and women, as well as people from non-binary categories, is an important limitation that should be addressed to obtain more applicable findings in LBD.},
}

@article {pmid41261421,
year = {2025},
author = {Etani, H and Takatori, S and Wang, W and Omi, J and Amiya, Y and Akahori, A and Watanabe, H and Sonn, I and Okano, H and Hara, N and Hasegawa, M and Miyashita, A and Kikuchi, M and Ikeuchi, T and Morishima, M and Saito, Y and Murayama, S and Saito, T and Saido, TC and Takai, T and Ohwada, T and Aoki, J and Tomita, T},
title = {Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {248},
pmid = {41261421},
issn = {1758-9193},
mesh = {*Microglia/metabolism/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice ; *Receptors, G-Protein-Coupled/agonists/metabolism ; Alzheimer Disease/metabolism/pathology ; Phagocytosis/drug effects ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {BACKGROUND: Microglia play a crucial role in brain homeostasis through phagocytosis of amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. The balance between Aβ production and clearance is critical for AD pathogenesis, with impaired clearance mechanisms potentially contributing to disease progression. G-protein coupled receptor 34 (GPR34), a microglia-enriched Gi/o-coupled receptor, is highly expressed in homeostatic microglia and may regulate phagocytic functions, yet its role in Aβ clearance remains poorly understood.

METHODS: Using flow cytometry-based assays, we investigated the effect of a selective GPR34 agonist (M1) on Aβ uptake in mouse primary microglia and human induced pluripotent stem cell-derived microglia. We evaluated uptake specificity across different Aβ species and phagocytic substrates, and measured intracellular cyclic adenosine monophosphate (cAMP) levels to determine the signaling mechanism. We performed in vivo studies using human amyloid precursor protein knock-in mice with intrahippocampal M1 injections. Additionally, we analyzed GPR34 expression in Japanese AD patient brain samples using single-nucleus RNA sequencing and examined age-dependent expression changes across multiple datasets.

RESULTS: M1 specifically enhanced uptake of Aβ fibrils through reduction of intracellular cAMP levels, without affecting monomeric or oligomeric Aβ internalization. Gpr34 knockdown experiments confirmed GPR34 as the molecular target of M1. An intrahippocampal injection of M1 significantly increased microglial Aβ uptake in vivo, an effect that required functional TREM2 signaling. GPR34 expression was significantly reduced in microglia from AD patients and showed age-dependent decline in both humans and mice.

CONCLUSIONS: Our findings identify GPR34 as a promising therapeutic target for enhancing microglial Aβ clearance and highlight the potential of GPR34 agonists for AD treatment. The age-dependent decline in GPR34 expression may contribute to reduced Aβ clearance efficiency in aging brains, exacerbating amyloid accumulation. Pharmacological activation of GPR34 represents a novel strategy to counteract impaired Aβ clearance in both aging and AD brains, potentially modifying disease progression through enhancement of microglial phagocytic function.},
}

*Microglia/metabolism/drug effects
Animals
*Amyloid beta-Peptides/metabolism
Humans
Mice
*Receptors, G-Protein-Coupled/agonists/metabolism
Alzheimer Disease/metabolism/pathology
Phagocytosis/drug effects
Mice, Transgenic
Male
Mice, Inbred C57BL
Cells, Cultured

@article {pmid41261317,
year = {2025},
author = {Zhou, R and Tian, G and Yu, J and Wang, R and Peng, N and Guo, X and Li, R},
title = {Echinacoside Improves Memory Function and Bone Mineral Density in the Aged SAMP8 Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {102},
pmid = {41261317},
issn = {1559-1182},
mesh = {Animals ; Male ; Mice ; *Bone Density/drug effects ; *Aging/drug effects/pathology ; Disease Models, Animal ; *Memory/drug effects ; *Glycosides/pharmacology/therapeutic use ; Osteoporosis/drug therapy ; },
abstract = {Alzheimer's disease (AD) and osteoporosis (OP) are prevalent age-related degenerative diseases that often coexist. Echinacoside (ECH) has been extensively studied for its potential to mitigate AD and bone mineral density (BMD) loss. This study aimed to evaluate the simultaneous therapeutic effects of ECH on AD-OP comorbidity using the senescence-accelerated mouse-prone 8 (SAMP8) model, which exhibits both age-related memory deficits and bone metabolism abnormalities. Six-month-old male SAMP8 mice (n = 8-9) were used as the model group, while age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice served as normal controls. SAMP8 mice were administered ECH intragastrically (100 mg/kg/day) for 10 weeks, while control groups received saline. Behavioral tests, including the open field test (OFT), novel object recognition test (NORT), and Morris Water Maze (MWM), assessed locomotor ability, emotionality, and cognitive functions. Bone microstructure was evaluated using micro-computed tomography (micro-CT), and pathological changes in the brain were analyzed via Western blotting and immunofluorescence. As compared to SAMR1 mice, SAMP8 mice exhibited significant locomotor activity issues, impaired memory (P < 0.05), glial activation (P < 0.01), reduced trabecular bone number (P = 0.007), and altered trabecular separation (P = 0.040). ECH treatment improved memory function and inhibited glial activation (P < 0.05). Bone-related parameters showed that ECH intervention had a trend of improvement in bone health, but this did not reach statistical significance. The SAMP8 model exhibits key features of both AD and OP, making it a valuable tool for investigating their comorbidity and underlying mechanisms. ECH improves cognitive functions and alleviates bone loss, indicating its potential as a therapeutic candidate for AD-OP comorbidity.},
}

Animals
Male
Mice
*Bone Density/drug effects
*Aging/drug effects/pathology
Disease Models, Animal
*Memory/drug effects
*Glycosides/pharmacology/therapeutic use
Osteoporosis/drug therapy

@article {pmid41261299,
year = {2025},
author = {Zhang, R and Wu, K and Yang, Q and Kong, M and Guo, L and You, Q},
title = {Hyperprolactinemia and Brain Health: Exploring the Gut-Brain Axis and Therapeutic Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {101},
pmid = {41261299},
issn = {1559-1182},
mesh = {Humans ; *Hyperprolactinemia/therapy/metabolism ; *Brain/pathology/metabolism ; Animals ; *Gastrointestinal Tract ; Gastrointestinal Microbiome/physiology ; Prolactin/metabolism ; *Brain-Gut Axis/physiology ; },
abstract = {Prolactin is a pituitary anterior lobe hormone that plays a crucial role in milk secretion from the mammary glands. Hyperprolactinemia is a common endocrine disorder characterized by abnormally elevated levels of prolactin in the serum. Recent research findings indicate that prolactin also exerts important physiological effects beyond lactation, including effects on brain health and the central nervous system. The gut-brain axis has become an important area of neuroscience research, providing insights into the complex interactions between the gastrointestinal system and the central nervous system. Future research may involve developing new probiotic therapies or optimizing the gut microbiota through dietary and lifestyle interventions. In addition, understanding the mechanisms by which hyperprolactinemia contributes to various neurological disorders and targeting prolactin for treatment are crucial areas of research. Therefore, this study aimed to investigate the correlation between hyperprolactinemia and brain health from the perspective of the gut-brain axis, with the goal of discovering new approaches for preventing and treating neurodegenerative and mental health conditions. This synthesis highlights potential strategies for future therapeutic interventions.},
}

Humans
*Hyperprolactinemia/therapy/metabolism
*Brain/pathology/metabolism
Animals
*Gastrointestinal Tract
Gastrointestinal Microbiome/physiology
Prolactin/metabolism
*Brain-Gut Axis/physiology

@article {pmid41261295,
year = {2025},
author = {Kritika, and Sood, R and Sanjay, and Lee, HJ},
title = {Nobiletin Reduces LPS-Induced Neuroinflammation through TLR4/MyD88/NF-κB and Oxidative Stress via Nrf2/HO-1 Signaling in Human Microglial HMC3 Cells.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {103},
pmid = {41261295},
issn = {1559-1182},
support = {GCU-202401020001//Gachon University research fund of 2023 (GCU-202401020001)/ ; (project No. RS-2022-RD010230)//Cooperative Research Program for Agriculture Science and Technology Development (project No. RS-2022-RD010230), Rural Development Administration, Republic of Korea./ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Myeloid Differentiation Factor 88/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Toll-Like Receptor 4/metabolism ; *Signal Transduction/drug effects ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; *Heme Oxygenase-1/metabolism ; *Flavonols/pharmacology ; *Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology ; *Flavones/pharmacology ; Cell Line ; Inflammation/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; },
abstract = {Neuroinflammation and oxidative stress (OS) are the major contributors to the onset and progression of neurodegenerative diseases (NDs), where microglial activation and dysregulated inflammatory signaling exacerbate neuronal injury. Nobiletin (NOB), a polymethoxylated flavonoid abundant in citrus fruits, has been reported to possess excellent bioactivities; however, its effects in combating inflammation and OS in human microglial cells (HMC3) have not been comprehensively examined. In this study, we investigated the effects of NOB on lipopolysaccharide (LPS)-induced inflammatory and oxidative responses in HMC3 cells. The HMC3 cells exposed to LPS (1 µg/mL) in the presence/absence of NOB (5, 10, 20, and 40 µM) for 24 h showed that NOB could attenuate LPS-induced cytotoxicity. NOB treatment attenuated LPS-induced upregulation of pro-inflammatory cytokines including interleukin (IL)-1β, and IL-6, and suppressed activation of the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa-light-chain-enhancer of activated B (TLR4/MyD88/NF-κB) pathway. NOB enhanced the protein expression levels of TLR10, a negative regulator of TLR4-mediated inflammatory signaling. In addition, NOB increased the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression, along with other antioxidants including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), leading to reduced intracellular reactive oxygen species (ROS). These findings suggest that NOB has promising anti-inflammatory and antioxidant effects in an in vitro model of LPS-induced neuroinflammation, potentially through modulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways. However, further in vivo studies are needed to validate these effects and explore NOB's potential as a candidate for therapeutic development in NDs.},
}

Humans
*Oxidative Stress/drug effects
*Myeloid Differentiation Factor 88/metabolism
*NF-E2-Related Factor 2/metabolism
*Toll-Like Receptor 4/metabolism
*Signal Transduction/drug effects
Lipopolysaccharides
*NF-kappa B/metabolism
*Microglia/drug effects/metabolism/pathology
*Heme Oxygenase-1/metabolism
*Flavonols/pharmacology
*Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology
*Flavones/pharmacology
Cell Line
Inflammation/metabolism/drug therapy
Reactive Oxygen Species/metabolism

@article {pmid41260559,
year = {2025},
author = {Peng, D and Wu, L and Zhang, L and Chen, H and Hu, B and Zhang, Q and Huang, Y},
title = {haFGF14-154 attenuates Aβ1-42-induced neurotoxicity by facilitating BDNF maturation in a neuron-astrocyte co-culture system.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104056},
doi = {10.1016/j.mcn.2025.104056},
pmid = {41260559},
issn = {1095-9327},
abstract = {haFGF14-154 improves cognitive impairment in animal models of Alzheimer's disease (AD), but the effects and mechanisms of astrocytes on the neuroprotection mediated by haFGF14-154 remain unclear. Here, a neuron-astrocyte co-culture system was established to investigate the functions of astrocytes. The results showed that astrocytes strengthened the protective effect of haFGF14-154 on Aβ1-42-treated neurons. This enhanced protective function of haFGF14-154 correlates with phenotypic transition in astrocytes, as demonstrated by the suppression of Aβ1-42-induced A1-like genes and the elevation of A2-like markers in vitro. These observations are consistent with the reduction of GFAP and C3 levels in the hippocampus and prefrontal cortex of APP/PS1 mice treated with haFGF14-154. haFGF14-154 modified the function of astrocytes by activating the AKT/CREB/BDNF pathway, thereby promoting neurite growth. Moreover, haFGF14-154 up-regulated the expression of Furin and MMP9 in astrocytes, leading to the processing of pro-BDNF. This effect was replicated in APP/PS1 mice administered with haFGF14-154. Compared to the Aβ group, the BDNF level in the co-culture system supernatant was increased, while the IL-1β level was decreased following haFGF14-154 treatment. Additionally, haFGF14-154 inhibited neuronal apoptosis in the co-culture system, as evidenced by a decrease in pro-BDNF/P75[NTR], an increase in Bcl-2, and a reduction of Bad and Cleaved-caspase-3. In conclusion, current results demonstrate that astrocytes are crucial for mediating the protective effect of haFGF14-154 against neuronal damage, and underline the importance of the AKT/CREB/BDNF pathway in promoting neurite growth and attenuating neuronal apoptosis.},
}

@article {pmid41260370,
year = {2025},
author = {Xiao, K and Sayed, H and Xing, J and Zhang, XY and Ai, J and Kirichek, E and Le, GH and Wong, S and Valentino, K and Teopiz, KM and Vinberg, M and Rosenblat, JD and Lo, HKY and Zhang, MC and McIntyre, RS},
title = {The effects of Lithium on Beta-amyloid deposition and tau phosphorylation: A systematic review.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120721},
doi = {10.1016/j.jad.2025.120721},
pmid = {41260370},
issn = {1573-2517},
abstract = {BACKGROUND: Current anti-amyloid treatments often cause amyloid-related imaging abnormalities in the treatment of Alzheimer's disease (AD). Lithium demonstrates neuroprotective and neurotrophic effects, and preclinical studies indicate it reduces intracerebral amyloid deposition and tau phosphorylation. This systematic review evaluates lithium's effects on beta-amyloid, tau, and cognitive deficits in major neurocognitive disorders.

METHODS: A systematic review of primary research was conducted using Embase, PsycInfo, MEDLINE, and PubMed databases from inception to September 2024, following PRISMA criteria. Animal and adult human studies evaluating lithium monotherapy's effects on AD were included.

RESULTS: Long-term low-dose lithium treatment demonstrates inconsistent efficacy in lowering intracerebral amyloid deposition and reversing AD-related cognitive deficits in preclinical and clinical trials. Lithium potentially slows amyloid plaque formation in pre-plaque stages through increasing heat shock proteins and suppressing protein synthesis in preclinical trials. Intracerebral lithium concentrations above 1 mM reduced phosphorylated tau through promoting tau ubiquitination and inhibiting CDK5 signalling in preclinical trials.

LIMITATIONS: AD currently needs a comprehensive animal model accurately representing human AD symptoms and progression, and more clinical trials are needed. Several included studies utilize peripheral lithium administration, which complicates assessment of effective intracerebral concentrations.

CONCLUSIONS: Lithium potentially reduces intracerebral amyloid deposition and tau phosphorylation in AD animal models and may reverse associated cognitive deficits. Further research should seek to replicate similar findings in larger samples and explore lithium's optimal dosage range in promoting intracerebral amyloid clearance.},
}

@article {pmid41260286,
year = {2025},
author = {Altındağ, F and Bayır, MH and Alhalboosi, JKI and Yıldızhan, K},
title = {Syringic acid mitigates scopolamine-induced cognitive impairment by regulating PSD-95 and GSK-3β and by preventing neurodegeneration in an Alzheimer-like rat model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115556},
doi = {10.1016/j.expneurol.2025.115556},
pmid = {41260286},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a disorder characterized by progressive cognitive impairment. Syringic acid (SA) is a phenolic compound with many beneficial effects, such as antioxidant, anti-inflammatory, anti-diabetic, anti-carcinogenic, and neuroprotective. Our study aimed to investigate the effects of SA (50 mg/kg/day) on scopolamine (SCO)-induced AD-like condition in rats. Immunohistochemical evaluation was performed using antibodies to postsynaptic density protein 95 (PSD-95), Glycogen synthase kinase-3β (GSK-3β), TNF-α, and caspase-3. The hippocampus was stained with Hematoxylin-Eosin, and the total number of hippocampal neurons and hippocampal volume were calculated using the stereological method. The Y-maze task behavioral test was performed. SCO decreased PSD-95 expression while increasing GSK-3β, TNF-α, and caspase-3 expression. SA treatment increased PSD-95 expression while decreasing GSK-3β, TNF-α, and caspase-3 expression. Compared to the control group, the number of hippocampal neurons was significantly decreased in the Alzheimer's group, but the number of neurons in the SA group was significantly higher than in the Alzheimer's group. Hippocampal volume was lower in the Alzheimer's group, although there was no statistical difference between the groups. SA also improved SCO-induced cognitive impairment. Our study findings suggest that SA may mitigate SCO-induced cognitive impairment in the AD rat model, modulating PSD-95 and GSK-3β and decreasing neuroinflammation and apoptosis.},
}

@article {pmid41259985,
year = {2025},
author = {Lin, C and Li, Q and Liu, G and Xi, Z and Yan, X and Li, S and He, L and Bai, P},
title = {Fe3O4@MoS2@Au-Ag microsphere-based ultrasensitive immunobiosensor for the early diagnosis of Alzheimer's disease.},
journal = {Talanta},
volume = {299},
number = {},
pages = {129127},
doi = {10.1016/j.talanta.2025.129127},
pmid = {41259985},
issn = {1873-3573},
abstract = {Alzheimer's Disease (AD), a most common neurodegenerative disease, has aroused people's great attention. Amyloid-β 1-42 (Aβ42) from serum/plasma has been listed as Core 1 biomarker in diagnostic guide and explore an ultrasensitive detection method of Aβ42 is of great significance for early AD diagnosis and treatment. Herein, an ultrasensitive fluorescent biosensor for Aβ42 detection is designed, which is composed of Fe3O4@MoS2 microsphere and Au-Ag alloy. Compared with typical single gold nanoparticles in traditional fluorescent biosensor, alloy nanoparticles can generate a stronger electromagnetic field to enhance the fluorescence of quantum dots via surface plasmon resonance, achieve the effect of signal amplification. Importantly, our design significantly improved the limit of detection to 11 ag/mL, with a linear response ranging from 0.1 to 10[4] fg/mL. Moreover, by replacing the detection antibody in the biosensor, it can also be applied to other common AD biomarkers, such as Aβ40 (linear range: 0.1 to 10[5] fg/mL, LOD: 61 ag/mL) and total Tau protein (linear range: 0.1 to 10[5] fg/mL, LOD: 40 ag/mL). The biosensor exhibited excellent performance in both spiked and real serum samples. This fluorescent biosensor based on Au-Ag alloy strategy with ultra-sensitivity and good selectivity, provides a reliable solution for AD's early diagnosis.},
}

@article {pmid41261258,
year = {2025},
author = {Rahmani, D and Chodari, L and Kakallahpour, M and Niknam, Z},
title = {Therapeutic Potential of Sodium Butyrate in Neurological and Psychiatric Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {90},
pmid = {41261258},
issn = {1559-1182},
mesh = {Humans ; *Mental Disorders/drug therapy ; Animals ; *Butyric Acid/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal loss associated with neuroinflammation, oxidative stress, and epigenetic dysregulation. Emerging evidence suggests that histone deacetylases (HDACs) are overexpressed in these conditions, making HDAC inhibitors (HDACIs) like sodium butyrate (NaB) promising candidates for therapeutic intervention. In addition, NaB has shown beneficial effects in various psychiatric disorders, including depression, anxiety, and schizophrenia, suggesting a broader neurotherapeutic potential. This review synthesizes findings from various in vitro and in vivo studies investigating the mechanisms and therapeutic applications of NaB, in both neurological and psychiatric disorders. We focus on its role as an HDACI, its impact on histone acetylation and gene expression, its ability to modulate gut microbiota, and its capacity to cross the blood-brain barrier (BBB) to exert neuroprotective effects. NaB demonstrates anti-inflammatory, antioxidant, anti-apoptotic, and neurotrophic properties, contributing to improved cognitive, motor, and behavioral outcomes in multiple models of central nervous system (CNS) dysfunction. Accumulating evidence supports its efficacy not only in NDDs but also in mental health disorders, highlighting its potential as a complementary treatment alongside conventional therapies. Given its multifaceted mechanisms and favorable safety profile, NaB holds promise as a novel therapeutic agent across a spectrum of neurological and psychiatric conditions. Further clinical investigation is warranted to fully establish its translational value.},
}

Humans
*Mental Disorders/drug therapy
Animals
*Butyric Acid/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy
Histone Deacetylase Inhibitors/therapeutic use/pharmacology

@article {pmid41261002,
year = {2025},
author = {Canney, M and Bouchoux, G and Carpentier, A and De Rossi, P},
title = {Repeated blood-brain barrier opening using low-intensity pulsed ultrasound mitigates amyloid pathology.},
journal = {Ultrasound in medicine & biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ultrasmedbio.2025.10.008},
pmid = {41261002},
issn = {1879-291X},
abstract = {OBJECTIVE: The delivery of large molecules to the pathological brain is one of the main obstacles in the development of disease-modifying drugs. This is partly due to the presence of the blood-brain barrier (BBB), which blocks the free passage of lipophobic molecules and those larger than 400 Da. One strategy to bypass this natural barrier is to use low-intensity pulsed ultrasound to oscillate circulating micro-sized microbubbles, which then exert mechanical stress on the vessel walls. This procedure allows for temporary disruption of the BBB and enhanced local delivery of therapeutics from the blood to the brain parenchyma. In this study, the effect of repeated BBB opening on neuroinflammation in a healthy mouse model was first explored, followed by the effect of repeated opening on amyloid-beta (Aβ) pathology in an Alzheimer's disease model.

METHODS: A cohort of wild-type mice was used to determine the effect of a single BBB opening session mediated by ultrasound/microbubbles (US/MBs) on the inflammatory profile via real-time quantitative polymerase chain reaction on brain extracts at 2, 4, 8 and 15 d post-opening. A second cohort of ARTE10 mice, a mouse model for Aβ pathology, was treated with a different sequence of repeated US/MB-mediated BBB opening to explore the effect on Aβ pathology. Tissues were also analyzed for immune cell infiltration, microglia and astrocyte activation, as well as inflammatory response.

RESULTS: Our results demonstrate that opening the BBB leads to a mild inflammatory response in wild-type animals. However, repeated opening of the BBB in the ARTE10 model resulted in a mild decrease in Aβ pathology, along with a mild increase in growth factor.

CONCLUSION: Altogether, this study suggests that sonication is not only a safe method to deliver therapeutics to the brain but could also have synergistic effects in the treatment of neurodegenerative disease.},
}

@article {pmid41260522,
year = {2025},
author = {Park, JK and Kim, HG and Lee, JS and Joo, JH and Yoo, HR},
title = {Traditional Herbal Medicine Ga-Mi Gongjindan Improves Muscarinic Cholinergic Dysfunction through Regulation of BDNF/CREB Signaling Pathway Using a Scopolamine-Induced Cognitive Impairment of Mouse Model.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111644},
doi = {10.1016/j.brainresbull.2025.111644},
pmid = {41260522},
issn = {1873-2747},
abstract = {BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by progressive memory loss and cognitive dysfunction, often linked to cholinergic system deterioration and hippocampal oxidative stress. Current pharmacological treatments offer only modest symptomatic relief and are often accompanied by adverse effects. In traditional Korean medicine, Ga-Mi Gongjindan (GJD), a modified formulation of Gongjindan, has long been used for enhancing cognitive function, but its neuropharmacological basis remains largely unexplored.

OBJECTIVE: This study aimed to investigate the neuroprotective potential and underlying mechanisms of GJD in a murine model of scopolamine-induced cognitive impairment, which mimics aspects of muscarinic cholinergic dysfunction observed in Alzheimer's disease (AD).

METHODS: C57BL/6J mice were administered GJD or tacrine (positive control) for 14 days. Cognitive impairment was induced by a single intraperitoneal injection of scopolamine (2mg/kg), and behavioral analysis was assessed using the Morris Water Maze. Hippocampal tissues were analyzed for markers of oxidative stress, inflammation, cholinergic function, and neurotrophic signaling by focusing on the BDNF/CREB signaling pathway.

RESULTS: GJD treatment significantly improved spatial learning and memory performance. It restored cholinergic function by reducing acetylcholinesterase (AChE) activity and increasing choline acetyltransferase (ChAT) levels. GJD also suppressed oxidative stress and neuroinflammation and markedly enhanced hippocampal expression of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and their receptors (TrkA, TrkB, and M1 mAChR).

CONCLUSION: GJD exerted significant neuroprotective effects in a scopolamine-induced model of cognitive dysfunction, potentially via modulation of cholinergic and BDNF/CREB signaling pathways. These findings provide a scientific rationale for the traditional use of GJD in cognitive disorders and support its further development as a candidate for treating neurodegenerative diseases such as AD.},
}

@article {pmid41260167,
year = {2025},
author = {Wang, X and Li, W and Liu, X and Liang, J and Wang, L and Liu, G and Liu, Y and Song, M and Li, Z and Guo, Y and Li, S and Fu, N and Zhang, B},
title = {Celastrol as a neuroprotective drug: current status and challenges.},
journal = {International immunopharmacology},
volume = {168},
number = {Pt 2},
pages = {115846},
doi = {10.1016/j.intimp.2025.115846},
pmid = {41260167},
issn = {1878-1705},
abstract = {Neurological disorders are increasing worldwide, imposing a major social and economic burden. Therefore, there is an urgent need to explore effective treatment methods to alleviate neurological disorders. Celastrol, derived from the traditional Chinese medicine Tripterygium wilfordii Hook. f., has been shown in multiple studies to exhibit promising neuroprotective effects in neurodegenerative, including Parkinson's disease, Alzheimer's disease, and spinal cord injury. The targets or pathways through which celastrol exerts its neuroprotective effects are diverse. This paper primarily focuses on in vivo animal models (such as Parkinson's disease mouse models, Alzheimer's disease mouse models) and in vitro cell models (such as neuronal cell lines, primary cultured neurons) experiments to comprehensively summarize the molecular mechanisms underlying celastrol's neuroprotective effects. Celastrol exerts its neuroprotective effects through pathways such as reducing inflammation, activating the autophagy-lysosome pathway, and inhibiting ferroptosis. Additionally, we discuss the current challenges faced by celastrol and potential strategies to address them. Collectively, these findings highlight celastrol as a promising therapeutic candidate, although further pharmacokinetic optimization and clinical validation are essential.},
}

@article {pmid41258757,
year = {2025},
author = {Saini, TC and Randhawa, S and Bathla, M and Nisha, A and Teji, N and Acharya, A},
title = {Nanoengineered Polyphenol-Quantum Dot Conjugates Inhibit Biofilm Protein-Aβ42 Heterotypic Fibrillogenesis, Restore Synaptic Transmission, and Suppress Apoptosis in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00467},
pmid = {41258757},
issn = {1948-7193},
abstract = {The gut microbiota influences neurodegenerative disease progression, including Alzheimer's disease (AD), through microbial metabolites like amyloids in bacterial biofilms, such as the curli protein in Eshcherichia coli biofilm. In this context, the study focuses on two key aspects, namely, (i) how cross-kingdom bacterial biofilm proteins accelerate Aβ42 aggregation and induce neurotoxicity and (ii) whether a nanochaperone with hydrophobic sheets and hydrophilic polyphenolic moieties could inhibit cross-seeded aggregation. Considering this, we chemically synthesized and further characterized gallic acid-conjugated molybdenum disulfide quantum dots (GA@MoS2 QDs, ∼9.6 ± 4.2 nm) using spectroscopy and microscopy techniques, which showed ∼1.84-fold reduction in E. coli biofilm thickness, indicating interaction with biofilm components. The presence of the curli protein in E. coli was confirmed by dot blot and MALDI-TOF studies. Subsequent biophysical studies showed that isolated E. coli biofilm protein accelerated Aβ42 aggregation (heterotypic) by ∼6.76-fold, while GA@MoS2 QDs reduced this heterotypic aggregation by ∼9.49-fold reduction in Aβ42+ECBFP fluorescence relative to Aβ42 aggregates. In vitro studies with SH-SY5Y cells showed that heterotypic protein aggregation led to increased ROS production, intracellular calcium influx, and apoptosis induction, which were mitigated by GA@MoS2 QDs. The neuroprotective effect of GA@MoS2 QDs was also studied on Caenorhabditis elegans. Overall, the present studies suggested that the bacterial amyloid proteins may play a crucial role in Aβ42 aggregation, suggesting that targeting coaggregation could provide a novel therapeutic approach for the treatment of early onset AD.},
}

@article {pmid41258645,
year = {2025},
author = {Katsuse, K and Kakinuma, K and Niimi, Y and Iseki, C and Kawakami, N and Ota, S and Kawamura, A and Ogawa, N and Yano, S and Kakumoto, T and Takao, H and Hamada, M and Kanno, S and Toda, T and Suzuki, K},
title = {Lecanemab for posterior cortical atrophy: Two contrasting cases.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/13854046.2025.2590527},
pmid = {41258645},
issn = {1744-4144},
abstract = {OBJECTIVE: This study aimed to evaluate the clinical implications, limitations, and potential risks of lecanemab treatment for posterior cortical atrophy (PCA) by conducting a comparative analysis of two cases.

METHOD: We retrospectively analyzed two patients with biomarker-confirmed PCA-pure who met the eligibility criteria for lecanemab. Clinical history, neuropsychological profiles, imaging findings, and treatment outcomes for more than 1 year were comprehensively reviewed.

RESULTS: At treatment initiation, Patients 1 and 2 were one year post-onset and five years post-onset, respectively, with comparable baseline Mini-Mental State Examination (25-26) and Clinical Dementia Rating (0.5) scores. Patient 1, who exhibited prominent agraphia with left-dominant parieto-occipital atrophy, began lecanemab early and maintained stable daily functioning despite a gradual decline in reading, figure copying, and visual cancelation tasks. Patient 2, with right-dominant posterior atrophy and more severe visuospatial deficits, including simultanagnosia and prosopagnosia, developed parkinsonism and hallucinations after treatment initiation, followed by rapid functional decline, possibly due to mixed pathology, ultimately leading to treatment discontinuation. Patient 1 reported high treatment satisfaction, whereas Patient 2 expressed regret.

CONCLUSION: These cases raise concerns regarding the direct application of treatment eligibility criteria developed for typical Alzheimer's disease to PCA. Clinical decision-making in PCA requires visual cognition-specific assessments that are less vulnerable to floor effects and tailored to phenotypic heterogeneity and hemispheric lateralization. Coexisting pathologies may influence the treatment response and complicate the interpretation of outcomes. A tailored, multimodal approach that integrates longitudinal neuropsychological assessments with advanced imaging is essential to ensure appropriate use of disease-modifying therapies for PCA.},
}

@article {pmid41258002,
year = {2025},
author = {Yang, C and Wang, P and Zhu, Z and Wu, H and Su, Q and Zhu, S and Shao, Y and Lin, H and Biswal, BB},
title = {Individualized functional connectome biomarkers predict clinical symptoms after rTMS treatment in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-025-03726-4},
pmid = {41258002},
issn = {2158-3188},
abstract = {Pharmacological treatments for Alzheimer's disease (AD) often show limited effectiveness, prompting growing interest in non-drug approaches such as repetitive transcranial magnetic stimulation (rTMS). However, the effects of rTMS can vary widely between individuals with AD, highlighting the need to better understand brain characteristics that may influence treatment response. In this study, we applied a personalized method to divide each participant's brain cortex into functionally meaningful regions based on their brain activity patterns, rather than relying on a standard brain template. Using this individualized brain mapping approach, we examined how rTMS changes functional connectivity (FC) across the brain. We further used support vector regression to estimate whether these individualized FC patterns could predict the severity of clinical symptoms. The results showed that rTMS significantly increased whole-brain individualized FC strength during resting state, with the most prominent effects observed in the default mode and visual networks (Cohen's d > 0.27, corrected p < 0.05). Importantly, the personalized FC features served as predictive biomarkers, demonstrating greater accuracy in forecasting clinical outcomes compared to the conventional group-based approach. These findings suggest that individualized brain connectivity holds significant potential for guiding personalized therapeutic strategies and improving treatment efficacy in AD.},
}

@article {pmid41257439,
year = {2025},
author = {Vázquez-Oliver, A and Pérez-García, S and Romero-Pérez, R and Pizarro, N and Galarraga-Shinin, D and Molina-Porcel, L and de la Torre, R and Maldonado, R and Ozaita, A},
title = {Targeting dysregulated CB1 receptors in a Down syndrome mouse model improves neurological outcomes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70874},
doi = {10.1002/alz.70874},
pmid = {41257439},
issn = {1552-5279},
support = {RTI2018-099282-B-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2021-123482OB-I00-/MICIN/AEI/10.13039/501100011033/FEDER//Ministerio de Ciencia, Innovación y Universidades/ ; PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033//Ministerio de Ciencia, Innovación y Universidades/ ; 1896_GRT-2019B//Fondation Jérôme Lejeune/ ; #2416_GRT-2024B//Fondation Jérôme Lejeune/ ; CA2018010//Bright Focus foundation/ ; RD16/0017/0020//Ministerio de Sanidad, Servicios Sociales e Igualdad/ ; 2017SGR-669//Departament de Recerca i Universitats, Generalitat de Catalunya/ ; 2017SGR-138//Departament d'Economia i Coneixement, Generalitat de Catalunya/ ; //Institució Catalana de Recerca i Estudis Avançats, ICREA-Acadèmia 2021/ ; },
mesh = {Animals ; *Down Syndrome/metabolism/drug therapy ; *Receptor, Cannabinoid, CB1/metabolism/antagonists & inhibitors ; Mice ; Disease Models, Animal ; *Hippocampus/metabolism/drug effects ; *Rimonabant/pharmacology ; Humans ; Male ; Female ; Alzheimer Disease/metabolism ; *Cannabinoid Receptor Antagonists/pharmacology ; Mice, Transgenic ; Middle Aged ; },
abstract = {INTRODUCTION: Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting cognitive function and increasing the risk of early-onset Alzheimer's disease (AD). The endocannabinoid system may serve as a therapeutic target for cognitive deficits by inhibiting cannabinoid type-1 receptor (CB1R) function.

METHODS: CB1R expression was analyzed in the hippocampi of aged DS-associated AD (DSAD) individuals and middle-aged Ts65Dn mice. Long-term oral treatment with the CB1R antagonist rimonabant was used to assess its effects on memory and neuroinflammation in the Ts65Dn mouse model of DS.

RESULTS: CB1R expression was significantly increased in both aged DSAD subjects (specifically in the dentate gyrus and CA2 posterior hippocampal subregions) and Ts65Dn mice. Long-term rimonabant treatment improved memory performance, normalized microglial morphology, and reduced plasma inflammatory markers in trisomic mice without preventing neuron decline.

DISCUSSION: These findings suggest that sustained CB1R inhibition may enhance cognitive function by modulating neuroinflammation, highlighting its therapeutic potential for cognitive impairments in DS.

HIGHLIGHTS: Cannabinoid type-1 receptor (CB1R) expression is increased in the posterior hippocampus of aged Down syndrome (DS) subjects and Ts65Dn mice. Long-term rimonabant treatment enhances memory in middle-aged Ts65Dn mice. CB1R inhibition shifts neuroinflammatory features in Ts65Dn mice. CB1R inhibition does not halt noradrenergic/cholinergic neurodegeneration in Ts65Dn. CB1R inhibition presents potential for memory improvement in DS-related deficits.},
}

Animals
*Down Syndrome/metabolism/drug therapy
*Receptor, Cannabinoid, CB1/metabolism/antagonists & inhibitors
Mice
Disease Models, Animal
*Hippocampus/metabolism/drug effects
*Rimonabant/pharmacology
Humans
Male
Female
Alzheimer Disease/metabolism
*Cannabinoid Receptor Antagonists/pharmacology
Mice, Transgenic
Middle Aged

@article {pmid41257084,
year = {2025},
author = {Elshahary, A and Safwan, H and Abdelwaly, A and Arafa, RK and Helal, MA},
title = {Discovery of indole- and quinolone-based inhibitors of the mTOR/Akt/Pi3K pathway for the potential treatment of autism and certain types of cancer.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41257084},
issn = {2632-8682},
abstract = {Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the PI3K-related protein kinase family. It is an integral part of two functionally distinct protein complexes: mTOR complex 1 and mTOR complex 2. Its signaling pathway is linked to cell survival, growth, proliferation, and motility. Deregulation of the mTOR pathway has been reported in many types of cancer. Hence, mTOR is an attractive target for the treatment of certain cancers such as renal cell carcinoma and pancreatic tumors. In addition, hyperactivity in mTOR-mediated signaling is associated with the pathogenesis of autism spectrum disorder (ASD) and Alzheimer's disease. Recently, mTOR inhibitors have been considered as emerging pharmacotherapy for these disorders. In this research, we have used molecular modeling techniques to design three series of compounds, indoles, β-carbolines, and 4-aminoquinolines, targeting the ATP site of the mTOR kinase. Based on insights from molecular docking, we developed twenty eight derivatives of these scaffolds to explore the SAR and optimize their affinities. The prepared compounds were evaluated for their inhibitory activity against mTOR as well as other closely related kinases such as PI3K and AKt. To our delight, twenty compounds have shown sub-micromolar activities towards the mTOR kinase. Compounds HA-2l and HA-2c showed a superior IC50 of 66 and 75 nM, respectively, for mTOR, while being selective against AKt and Pi3K. Upon optimization, these selective inhibitors could be useful for the management of ASD due to their relatively higher safety and, hence, suitability for long-term use. On the other hand, derivatives HA-1e, HA-2g, and HA-3d exhibited high affinities for the three enzymes, suggesting their potential utility as anticancer agents. Also, the cytotoxicity of the most active compounds was assessed using different cell-lines. Compounds HA-2g, HA-2l, and HA-3d showed sub-micromolar inhibition, in the range of 0.610-0.780 μM, against the tested cancer cell lines MDA-MB231 and HCT-116. The discovery of a clinically useful mTOR inhibitor would represent a new hope for patients of two important non-communicable diseases, cancer and ASD.},
}

@article {pmid41257022,
year = {2025},
author = {Abdel-Magid, AF},
title = {Inhibitors of Stearoyl-Coenzyme A Desaturase 1 and 5 May Provide a Novel Therapeutic Strategy for the Treatment of Neurological Disorders and Brain Cancer.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {11},
pages = {2191-2193},
pmid = {41257022},
issn = {1948-5875},
abstract = {The invention in this patent application relates to heterocyclic compounds represented herein generally by formula 1. These compounds are inhibitors of stearoyl-coenzyme A desaturases (SCD1 and/or SCD5) and may provide a useful treatment for neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) as well as primary brain cancer such as glioblastoma (GBM).},
}

@article {pmid41257016,
year = {2025},
author = {Song, Z and Liang, SH},
title = {Novel 2H‑Pyrazolo[3,4‑d]thiazole Compounds Targeting NLRP3 for the Treatment of Neurodegenerative Diseases.},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {11},
pages = {2200-2201},
pmid = {41257016},
issn = {1948-5875},
abstract = {The invention discloses novel NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inhibitors featuring a 2H-pyrazolo-[3,4-d]-thiazole scaffold. These NLRP3 inhibitors exhibit significant potential as therapeutic candidates for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.},
}

@article {pmid41256885,
year = {2025},
author = {Cottrell, S and Yoon, S and Wei, X and Dickson, A and Wei, GW},
title = {Computational Drug Repurposing for Alzheimer's Disease via Sheaf Theoretic Population-Scale Analysis of snRNA-seq Data.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41256885},
issn = {2331-8422},
abstract = {Single-cell and single-nucleus RNA sequencing (scRNA-seq /snRNA-seq) are widely used to reveal heterogeneity in cells, showing a growing potential for precision and personalized medicine. Nonetheless, sustainable drug discovery must be based on a population-level understanding of molecular mechanisms, which calls for the population-scale analysis of scRNA-seq/snRNA-seq data. This work introduces a sequential target-drug selection model for drug repurposing against Alzheimer's Disease (AD) targets inferred from population-level snRNA-seq studies of AD progression in microglia cells as well as different cell types taken from an AD affected brain vascular tissue atlas, involving hundreds of thousands of nuclei from multi-patient and multi-regional studies. We utilize Persistent Sheaf Laplacians (PSL) to facilitate a Protein-Protein Interaction (PPI) analysis of AD targets inferred from differential gene expression (DEG), and then use machine learning models to predict repurpose-able DrugBank compounds for molecular targeting. We screen the efficacy of different DrugBank small compounds and further examine their central nervous system (CNS)-relevant ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity), resulting in a list of lead candidates for AD treatment. The list of significant genes establishes a target domain for effective machine learning based AD drug repurposing analysis of DrugBank small compounds to treat AD related molecular targets.},
}

@article {pmid41256774,
year = {2025},
author = {Yu, J and Bao, X and Shan, C and Yu, Z and Yu, Y and Wang, H and Zhang, Y},
title = {Traditional Chinese medicine's holistic approach: regulating microglia-driven neuroinflammation for the resolution of Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1691253},
pmid = {41256774},
issn = {1662-5102},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction, motor abnormalities, and memory disorders, with a persistently high and rising incidence. The pathological features of AD include the extracellular deposition of the amyloid beta peptide (Aβ), the accumulation of neurofibrillary tangles (NFTs), and neuroinflammation. Microglia (MG), the main immune cells in the central nervous system (CNS), can transform into different phenotypes. An imbalance in their phenotypic transformation may induce neuroinflammation and lead to neurological diseases, playing a central role in the onset and progression of AD.

PURPOSE: This article aims to briefly review the key role of microglia-mediated neuroinflammation in the pathogenesis of AD and to summarize and analyze the strategies of traditional Chinese medicine (TCM) for targeting microglia in AD treatment.

METHODS: Literature review and analysis were conducted to summarize the role of microglia-mediated neuroinflammation in AD pathogenesis and to collate TCM therapeutic strategies aimed at modulating microglia.

RESULTS AND CONCLUSION: Microglia-mediated neuroinflammation plays a central role in the pathological progression of AD. TCM demonstrates potential in intervening in AD neuroinflammation by regulating the microglial phenotype and function. These related therapeutic strategies warrant further summary and analysis.},
}

@article {pmid41256155,
year = {2025},
author = {Su, CW and Chen, K and Wu, T and Reiman, EM and Wang, Q and , },
title = {TAS2R38-Linked MGAM Expression in Alzheimer's Disease: A Novel Target for Precision Drug Repurposing.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.09.25334938},
pmid = {41256155},
abstract = {OBJECTIVE: TAS2R38 is a taste receptor implicated in innate immunity. Identifying its genetic connection with Alzheimer's disease (AD) could aid in developing new drugs or repurposing existing ones for treatment.

METHODS: We examined the relationship between TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 2,342). We investigated molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues from the Religious Orders Study/Memory and Aging Project (ROSMAP) (n = 947). We evaluated whether FDA-approved drugs targeting the identified gene could reduce dementia risk using 1:1 propensity score-matched groups in the National Alzheimer's Coordinating Center (NACC) study, comparing cognitive performance between drug-taking and non-taking patients with linear mixed-effects models (n = 76).

RESULTS: TAS2R38 supertasters were linked to reduced AD risk with advancing age in various AD biomarkers (P < 0.001). eQTL analysis connected the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (P < 0.001). Elevated MGAM expression was also associated with more severe Tau burdens (P < 0.05). A significant group difference was observed in clinical dementia rating (CDR) progression (P < 0.001) in various domains for individuals taking MGAM-inhibiting diabetes drugs (Acarbose and Miglitol) compared to the non-taking group.

INTERPRETATION: The genetic association between TAS2R38 and AD biomarkers implicates MGAM as a novel drug target with existing FDA-approved inhibitors. This supports the potential of TAS2R38 haplotypes in guiding precision drug repurposing strategies for AD, warranting clinical trials.},
}

@article {pmid41256144,
year = {2025},
author = {Yakoub, Y and Qiu, T and Peyrot, C and Salvadó, G and Villeneuve, S and Binette, AP and , },
title = {Trajectories of plasma biomarkers, amyloid-beta burden and cognitive decline in Alzheimer's disease: A Longitudinal ADNI Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.30.25337003},
pmid = {41256144},
abstract = {As novel amyloid-β targeted therapies emerge, plasma biomarkers have promising potential to serve as screening tools and as surrogate measures for treatment outcomes. Understanding longitudinal trajectories of these biomarkers and how their changes relate to changes in AD pathology and cognition is needed to help track treatment response and guide patient care. We analyzed data from 394 individuals in the ADNI-FNIH dataset who had plasma biomarkers available across 14 assays, Aβ-PET scans and cognitive assessments over a 10-year period. Plasma p-tau217, regardless of the assay used, had the greatest rate of change over time. This increase was related to concurrent increase in Aβ-PET burden only in individuals with low levels of Aβ. The rate of p-tau217 change, rather than its baseline level, was the strongest predictor of future Aβ-PET positivity. On the other hand, in individuals with elevated levels of Aβ, higher rate of change in p-tau217 was associated with faster cognitive decline. These findings highlight a "dual" role of plasma p-tau217 rate of change, being either predictive of accumulating Aβ pathology at early stages and of cognitive decline at later stages of the AD continuum.},
}

@article {pmid41256136,
year = {2025},
author = {Tang, AS and Zeng, BZD and Rankin, KP and Miller, B and Gorno-Tempini, ML and Seeley, WW and Rosen, HJ and Rabinovici, GD and Oskotsky, TT and Sirota, M and Pinheiro-Chagas, P},
title = {Characterizing Dementia Phenotypes from Unstructured EHR Notes with Generative AI and Interpretable Machine Learning.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.10.01.25336815},
pmid = {41256136},
abstract = {Dementia encompasses diverse clinical syndromes where diseases of the brain can manifest as impaired cognitive abilities, such as in Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). The diversity of symptom presentations often results in challenges in diagnosis. Crucial clinical information remains in unstructured narrative notes within electronic health records (EHRs). We leverage large language models (LLMs) for symptom phenotyping from notes in UCSF Information Commons, focusing on patients with expert dementia syndrome diagnosed from a multidisciplinary team of specialists from the UCSF Memory and Aging Center. We developed a pipeline to extract findings in a validated structured output, clustered into symptom groups, and then classified patients into syndromes with traditional machine learning paradigms. From over 9,000 cross-referenced patients and over 350,000 specialty-related notes, matched cohorts of bvFTD (122 patients) and AD (170) syndromes were identified. From notes, 12,637 distinct symptom phrases were extracted, with clustering analysis revealing 51 symptom groups. A logistic regression model separated AD and bvFTD with an AUC of 0.83. Disinhibition and obsessive-compulsive behaviors favored bvFTD, while anxiety and visuospatial abnormalities favored AD. This novel approach, combining LLM-based structured information extraction with traditional interpretable prediction paradigms, demonstrates a promising approach for enhanced symptom characterization in dementia. Our findings suggest potential future applications in improving diagnostic accuracy, developing prediction models, and optimizing treatment strategies in dementia care.},
}

@article {pmid41255958,
year = {2025},
author = {Biswas, P and Rahman, MH and Tabassum, A and Shoyshob, TZ and Jalouli, M and Islam Tareq, MM and Imtiaz, M and Dona, HA and Harrath, AH and Rahman, MA},
title = {Novel Drug Targets for Neurodegenerative Diseases of Elderly People to Develop Effective Therapeutics: A Comprehensive Analysis.},
journal = {Advances in pharmacological and pharmaceutical sciences},
volume = {2025},
number = {},
pages = {8847508},
pmid = {41255958},
issn = {2633-4690},
abstract = {Neurodegenerative diseases (NDs) represent an increasingly important burden of disease, particularly in the aging population. The etiology of NDs like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) is associated with progressive neuronal degeneration and a paucity of effective therapies. Accumulating evidence suggests that common and intersecting genetic and pathological pathways play a critical role in disease onset and progression, revealing new opportunities for target discovery. Here, we review promising therapeutic targets based on the convergence of genetics, molecular pathology, and cellular signaling in neurodegeneration. This narrative will focus on key proteins (amyloid-beta [Aβ], tau, and α-synuclein) and enzymes (acetylcholinesterase and asparagine endopeptidase [AEP]), including their pathological significance and therapeutic implications. N-Methyl-D-aspartate receptors (NMDARs) and cholinergic receptor subtypes are highlighted as important regulators of neurotoxicity, synaptic transmission, and inflammation. Emerging advances in genomics, neuroimaging, and drug delivery are poised to advance precision medicine strategies for early diagnosis and intervention. Important challenges remain, including the complexity of the blood-brain barrier (BBB), pathology heterogeneity, and the need for new biomarkers. We propose that a shift from phenotype-driven diagnoses to mechanistic, genetically informed approaches may improve treatment efficacy. Target identification, validation, and targeted delivery are critical considerations for the success of future therapeutic development. This integrated view will help to inform and improve drug discovery and personalized medicine approaches in the field of neurodegeneration.},
}

@article {pmid41255128,
year = {2025},
author = {Nilsson, P and Sörgjerd, K and Kakiya, N and Sasaguri, H and Watamura, N and Johansson, L and Shimozawa, M and Tsubuki, S and Zhou, Z and Loera-Valencia, R and Takamura, R and Sekiguchi, M and Pegel, A and Schulz, S and Saito, T and Iwata, N and Winblad, B and Saido, TC},
title = {Somatostatin receptor subtypes 1 and 4 regulate neprilysin, the major amyloid-β degrading enzyme in brain.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392782},
doi = {10.1177/13872877251392782},
pmid = {41255128},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) brains are characterized by increased levels of the pathogenic amyloid-β (Aβ) peptide, which accumulates into extracellular plaques. Finding a way to lower Aβ levels is fundamental for the prevention and treatment of AD. Neprilysin is the major Aβ degrading enzyme which is regulated by the neuropeptide somatostatin.ObjectiveWe here aimed at identifying the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin.MethodsWe used a combination of in vitro and in vivo approaches using a battery of generated Sst double knockout (dKO) mice. We investigated SST specificity of neprilysin regulation using primary neuronal cultures in combination with SST agonist treatments and neprilysin activity measurements. Brains from Sst dKO mice were analyzed for neprilysin and Aβ by biochemical and immunohistological means. Amyloid-beta precursor protein (App) knock-in mice were treated with SST1,4 agonist and its effects on neprilysin and Aβ were assessed by immunostaining and ELISA.ResultsWe show that neprilysin is regulated by SST1 and SST4 in a redundant manner. Sst1 and Sst4 dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency of Sst1 and Sst4 in App knock-in mice aggravates the Aβ pathology in hippocampus. As a first proof of concept towards an Aβ-lowering strategy involving neprilysin, we demonstrate that treatment with an SST1,4 agonist ameliorates the Aβ pathology.ConclusionsSST1 and SST4 redundantly regulate neprilysin in the hippocampus where it controls Aβ metabolism.},
}

@article {pmid41254914,
year = {2025},
author = {Mackey-Alfonso, SE and Barrientos, RM},
title = {Neuroinflammatory mechanisms linking high-fat diets to Alzheimer's disease vulnerability: Beyond the amyloid hypothesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70911},
doi = {10.1002/alz.70911},
pmid = {41254914},
issn = {1552-5279},
support = {RFAG028271/AG/NIA NIH HHS/United States ; R03AG067061/AG/NIA NIH HHS/United States ; R21AG071133/AG/NIA NIH HHS/United States ; //Ohio State University Presidential Fellowship/ ; },
mesh = {*Alzheimer Disease/metabolism/etiology/pathology ; Humans ; *Diet, High-Fat/adverse effects ; *Neuroinflammatory Diseases/metabolism ; Amyloid beta-Peptides/metabolism ; Toll-Like Receptor 4/metabolism ; Animals ; Brain/metabolism/pathology ; },
abstract = {As global life expectancy increases, Alzheimer's disease (AD) incidence is rising rapidly. While research has long focused on amyloid beta (Aβ) and tau pathology, recent controversies and limited clinical success of Aβ-targeting therapies have challenged their centrality in AD. Emerging evidence highlights neuroinflammation as an earlier and potentially more critical driver of disease, particularly in response to environmental and lifestyle factors. High saturated fat diets (HFD) are strongly associated with increased AD risk in both clinical and preclinical studies. This review examines how HFD promotes AD vulnerability via neuroinflammatory mechanisms, including toll-like receptor 4 activation and complement system overactivation, which contribute to synaptic loss and cognitive decline-often independent of Aβ burden and metabolic dysfunction. Short-term HFD exposure can rapidly induce neuroinflammation and impair memory, underscoring the direct impact of diet on brain health. These insights support a shift toward targeting immune pathways and synaptic preservation in AD prevention and treatment. HIGHLIGHTS: High saturated fat diets (HFDs) increases Alzheimer's disease risk independently of obesity or insulin resistance. Neuroinflammation is a key driver of HFD-induced cognitive decline. Toll-like receptor 4 (TLR4) activation links saturated fats to synaptic loss and memory deficits. HFDs promote complement-mediated microglial synaptic engulfment. Short-term HFD exposure rapidly impairs memory and increases brain inflammation.},
}

*Alzheimer Disease/metabolism/etiology/pathology
Humans
*Diet, High-Fat/adverse effects
*Neuroinflammatory Diseases/metabolism
Amyloid beta-Peptides/metabolism
Toll-Like Receptor 4/metabolism
Animals
Brain/metabolism/pathology

@article {pmid41254870,
year = {2025},
author = {Rathod, SS and Agrawal, YO},
title = {β-Caryophyllene Ameliorates STZ-Induced Alzheimer's Disease-Like Conditions in Rats via Modulation of Brain-Derived Neurotrophic Factor, Synaptic Plasticity, and Neuroinflammation.},
journal = {The European journal of neuroscience},
volume = {62},
number = {10},
pages = {e70317},
doi = {10.1111/ejn.70317},
pmid = {41254870},
issn = {1460-9568},
mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; *Neuronal Plasticity/drug effects ; Male ; *Polycyclic Sesquiterpenes/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Rats ; Rats, Sprague-Dawley ; Streptozocin/toxicity ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuroinflammation. Synaptic plasticity and neuroinflammation are hallmarks of AD, with their dysregulation forming a self-reinforcing cycle that aggravates neurodegeneration. Proinflammatory cytokines impair synaptic signaling by suppressing brain-derived neurotrophic factor (BDNF) expression and neuroplasticity markers, further compromising synaptic plasticity. β-Caryophyllene (BCP), a natural bicyclic sesquiterpene with anti-inflammatory and neuroprotective properties, may counteract these pathological processes. This study evaluated the effect of BCP in mitigating streptozotocin (STZ)-induced AD-like conditions in male Sprague-Dawley rats. Two doses of STZ (3 mg/kg) on Days 1 and 3 were administered intracerebroventricularly to induce AD-like pathology. Rats received BCP (10, 20 mg/kg, i.p.) or rivastigmine (2.5 mg/kg) for 28 days. Cognitive performance was assessed using the Barnes maze and novel object recognition tests. Hippocampal tissues were analyzed for BDNF expression, synaptic plasticity markers (e.g., synaptophysin, neural cell adhesion molecule [NCAM], and ciliary neurotrophic factor [CNTF]), neuroinflammatory markers (e.g., IL-1β, TNF-α, IL-6, COX2, and NF-κB), and oxidative stress markers. Histological (hematoxylin and eosin) and Golgi-Cox staining techniques were employed to evaluate neuronal integrity and synaptic organization. STZ-induced rats exhibited significant cognitive deficits, synaptic loss, and increased neuroinflammation. BCP treatment improved spatial learning and memory retention, increased BDNF expression, and restored synaptic plasticity markers. Furthermore, BCP attenuated neuroinflammation by reducing proinflammatory cytokine levels. Histopathology confirms normal hippocampal neuronal architecture in BCP-treated groups. These findings highlight the ability of BCP to modulate BDNF signaling, synaptic plasticity, and neuroinflammatory pathways, underscoring its potential as a multitarget therapeutic candidate for AD.},
}

Animals
*Brain-Derived Neurotrophic Factor/metabolism
*Neuronal Plasticity/drug effects
Male
*Polycyclic Sesquiterpenes/pharmacology
*Alzheimer Disease/drug therapy/chemically induced/metabolism
Rats
Rats, Sprague-Dawley
Streptozocin/toxicity
*Neuroinflammatory Diseases/drug therapy/metabolism
Hippocampus/drug effects/metabolism
*Neuroprotective Agents/pharmacology

@article {pmid41254247,
year = {2025},
author = {Kochman, U and Sitka, H and Kuźniar, J and Czaja, M and Kozubek, P and Beszłej, JA and Leszek, J},
title = {Targeted Nanoparticles for Drug Delivery Across the Blood-Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {75},
pmid = {41254247},
issn = {1559-1182},
mesh = {*Blood-Brain Barrier/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Nanoparticles/metabolism/chemistry ; Animals ; *Drug Delivery Systems/methods ; Drug Carriers ; },
abstract = {Alzheimer's disease (AD) presents important challenges for treatment. One significant factor that may reduce the effectiveness of therapy is the limited drug delivery to the brain due to the blood-brain barrier (BBB). Advancements in nanotechnology are offering innovative solutions to bypass this obstacle. This review highlights the role of targeted nanoparticles (NPs) as effective drug carriers across the BBB for both early and late stages of AD. The distinct pathophysiological traits of these stages-such as amyloid aggregation, abnormal accumulation of tau protein, neuroinflammation, and oxidative stress-are examined for their impact on therapy. The analysis includes lipid-based, polymeric, and inorganic NPs, exploring their unique properties for drug delivery. Strategies to target NPs to brain tissues affected by AD are discussed, emphasizing surface modifications to enhance BBB permeability. Uptake mechanisms like receptor-mediated and adsorptive-mediated transcytosis are detailed alongside safety, toxicity, and biocompatibility evaluations to assess clinical feasibility. Key findings indicate that targeted NPs significantly improve brain drug bioavailability and enable stage-specific therapeutic interventions, addressing challenges unique to early and late AD. Future research should focus on optimizing NP design for enhanced targeting specificity and minimizing long-term toxicity, ultimately paving the way for personalized nanomedicine approaches in AD treatment.},
}

*Blood-Brain Barrier/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
*Nanoparticles/metabolism/chemistry
Animals
*Drug Delivery Systems/methods
Drug Carriers

@article {pmid41252538,
year = {2025},
author = {Depp, C and Holden, J and Granholm, E},
title = {Digital Measurement of Subjective Experiences in Alzheimer Disease and Related Dementias (AD/ADRD).},
journal = {JMIR aging},
volume = {8},
number = {},
pages = {e71920},
doi = {10.2196/71920},
pmid = {41252538},
issn = {2561-7605},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; Caregivers/psychology ; Quality of Life ; Wearable Electronic Devices ; *Dementia/psychology ; },
abstract = {Symptoms such as loss of pleasure, agitation, and sadness are subjective experiences that contribute significantly to caregiver burden and health care costs in Alzheimer disease and related dementias (AD/ADRD). However, traditional self-report measures of subjective experiences are limited in AD/ADRD due to cognitive impairments and awareness. Passive sensing, which collects data without active participant input, has emerged as a promising approach to quantify aspects of subjective experiences. Smartphones, wearables, and in-home sensors can quantify mobility, physiology, speech, and social interaction markers of constructs relevant to AD/ADRD. Available research indicates potential but is largely at the proof-of-concept stage. In this Commentary, we discuss several roadblocks to future translation of passive sensing in measuring subjective experiences in AD/ADRD, including technical implementation, data harmonization, validation, ethical and privacy principles. Addressing these challenges could lead to transformative applications to care for AD/ADRD, enabling precise monitoring of behavioral symptoms and related treatment targets, ultimately improving quality of life for persons with AD/ADRD and their caregivers.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
Caregivers/psychology
Quality of Life
Wearable Electronic Devices
*Dementia/psychology

@article {pmid41251074,
year = {2025},
author = {Joshi, S and Chutia, P and Tripathi, SM},
title = {Paratonia in dementia: diagnosis and management strategies.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/17582024.2025.2591413},
pmid = {41251074},
issn = {1758-2032},
abstract = {Paratonia is a type of hypertonia with involuntary resistance to passive movement depending on the pace and force being applied. People with paratonia may find it challenging to modify their movements and posture. Limited awareness among healthcare professionals can lead to a delay in diagnosis and inadequate treatment. Here, we present two cases diagnosed with dementia due to Alzheimer's disease. The two patients developed stiffness in their bodies as the dementia progressed. Paratonia was diagnosed using the Paratonia Assessment Inventory. Severity of paratonia was assessed using the Modified Ashworth scale for paratonia (MAS-P). The caregiver's primary concern was the stiffness of the body, which created difficulties in routine care. Amantadine was initiated in both patients. Both patients demonstrated improvement in paratonia following amantadine treatment, with reduced stiffness and greater ease in caregiving tasks. The present case series highlights the role of amantadine in the management of paratonia and can contribute to the development of more treatment options.},
}

@article {pmid41250246,
year = {2025},
author = {Shang, J and Zhong, S and Shang, L and Zeng, Q and Zhao, S and Luo, X and Li, K and Zhang, X and Huang, P and Yan, Y and Liu, Z and Zhang, B and Chen, Y},
title = {Real-world application of lecanemab in early-stage alzheimer's disease: a single-center prospective cohort analysis.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {249},
pmid = {41250246},
issn = {1758-9193},
support = {82402209//National Natural Science Foundation of China/ ; 82271936//National Natural Science Foundation of China/ ; 82202090//National Natural Science Foundation of China/ ; 82271268//National Natural Science Foundation of China/ ; 82371190//National Natural Science Foundation of China/ ; LQ24H180002//Natural Science Foundation of Zhejiang Province/ ; LY24H090007//Natural Science Foundation of Zhejiang Province/ ; 2025C02113//Key Research and Development Program of Zhejiang Province/ ; },
abstract = {BACKGROUND AND OBJECTIVES: Lecanemab (Leqembi®) has been approved for the treatment of early Alzheimer’s disease (AD) patients. However, the safety and efficacy of lecanemab in clinical practice in Asia population remain unclear.

This prospective cohort study was conducted in a single center in Eastern China, including 76 early-stage AD participants treated with lecanemab. All participants underwent at least 1 lecanemab infusion.

RESULTS: The mean age was 66 years (65.53 ± 9.31), and 51 (67.1%) participants being female. A total of 49 (64.5%) participants were ApoE-ε4 carriers, including 34 (44.7%) heterozygotes and 15 (19.7%) homozygotes. Infusion-related side effects (IRSE), primarily occurred after the first infusion, were observed in 14 participants (18.4%). The most common IRSE were fever and fatigue. Until 9 Aug 2025, 58 participants had received treatment for more than 3 months, 44 for more than 6 months and 12 for more than 12 months. Amyloid-related imaging abnormalities (ARIA) were observed in 11 participants. Specifically, solitary ARIA-H (hemorrhage) was detected in 7 participants, while ARIA-E (edema) with or without cerebral micro-hemorrhage was identified in 4. Notably, all the 11 participants with ARIA were asymptomatic. Participants with isolated ARIA-H exhibited higher baseline Fazekas scores of PVWMHs (p = 0.008). Participants with a Clinical Dementia Rating Scale Global Score (CDR-GS) of 1 had a more rapid decline in Mini-Mental State Global Score (MMSE) scores as compared to those with a CDR-GS of 0.5. Following 12 months of lecanemab therapy, amyloid PET exhibited a significant reduction in brain amyloid burden.

CONCLUSION: These data support that lecanemab appears to be generally tolerated in Asian population. The IRSE and ARIA-E events were less common than the Clarity AD study.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01886-5.},
}

@article {pmid41251026,
year = {2025},
author = {Ahmad, N and Ambreen, N and Ayaz, M and Zainab, and Alam, A and Ahmad, I and Elhenawy, AA and Zghab, I and Shah, SAA and Ahmad, M},
title = {Synthesis, In Vitro Cholinesterase Inhibition, Molecular Docking, Density Functional Theory Analysis of Benzimidazole Based Hydrazone Schiff Bases.},
journal = {Journal of molecular recognition : JMR},
volume = {38},
number = {6},
pages = {e70012},
doi = {10.1002/jmr.70012},
pmid = {41251026},
issn = {1099-1352},
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Schiff Bases/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; *Hydrazones/chemistry/chemical synthesis/pharmacology ; *Benzimidazoles/chemistry/chemical synthesis/pharmacology ; Butyrylcholinesterase/chemistry/metabolism ; Acetylcholinesterase/chemistry/metabolism ; Molecular Dynamics Simulation ; Density Functional Theory ; Humans ; },
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are the main therapeutic targets for the treatment of neurodegenerative diseases, predominantly Alzheimer's disease. This work reports the synthesis, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of synthesized hydrazone Schiff base derivatives of benzimidazole. The compounds have been structurally deduced by means of HR-ESI-MS, [1]H-NMR and [13]C-NMR techniques and finally assessed for their in vitro AChE and BuChE inhibitory activities. All the compounds attributed notable inhibitory potential with IC50 values ranging from 34.7 ± 0.02 to 185.2 ± 2.47 μM for AChE and 40.8 ± 0.32 to 188.8 ± 2.47 μM for BuChE enzymes. The molecular docking and TD-DFT studies attributed that the compound with methoxy groups, specifically compound (7) displays increased electronic properties and strong dual binding to AChE and BuChE enzymes. Molecular dynamics (MD) simulations for the most active compound (7) were performed, which showed that compound (7) exploits the integral flexibility of AChE and BuChE to encourage conformational variations that lock both enzymes into a two-site inhibitory state. These compounds presented orbitals and favorable electrostatic profiles that improve the inhibitory potential. The results authenticate the SAR trends and highlight the significance of methoxy groups in planning potent cholinesterase inhibitors.},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology
Schiff Bases/chemistry/chemical synthesis/pharmacology
Molecular Docking Simulation
*Hydrazones/chemistry/chemical synthesis/pharmacology
*Benzimidazoles/chemistry/chemical synthesis/pharmacology
Butyrylcholinesterase/chemistry/metabolism
Acetylcholinesterase/chemistry/metabolism
Molecular Dynamics Simulation
Density Functional Theory
Humans

@article {pmid41250235,
year = {2025},
author = {Corbett, A and Sultana, J and Stych, K and Mills, R and Cummings, JL and Williams, G and Ismail, Z and Soto-Martin, M and Mintzer, J and Gauthier, S and Greig, NH and Noble, W and Killick, R and Lai, MKP and Routledge, C and Walsh, F and Fillit, H and Aarsland, D and Lane, R and Mills, K and Ballard, C},
title = {Drug repurposing for Alzheimer's disease: a Delphi consensus and stakeholder consultation.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {237},
pmid = {41250235},
issn = {1758-9193},
mesh = {*Drug Repositioning/methods ; *Alzheimer Disease/drug therapy ; Humans ; Delphi Technique ; Consensus ; Stakeholder Participation ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is an escalating global challenge, with more than 40 million people affected, and this number is projected to increase to more than 100 million by 2050. While amyloid-targeting antibody treatments (lecanemab and donanemab) are a significant step forward, the benefits of these therapies remain limited. This highlights the necessity for safe and effective compounds that offer greater therapeutic benefits to the majority of individuals with or at risk of AD. Drug repurposing allows for a cost-effective, time-efficient strategy to accelerate the availability of treatments, owing to the availability of safety information.

METHOD: This study focuses on the third iteration of the Delphi consensus programme aimed at identifying new high-priority drug candidates for repurposing in AD. An international expert panel comprising academics, clinicians and industry representatives was convened. Through a combination of anonymized drug nominations, systemic evidence reviews, iterative consensus rankings, and lay advisory inputs, drug candidates were evaluated and ranked based on rational, non-clinical, and clinical evidence and overall safety profiles.

RESULTS: Among the 80 candidates that were nominated by the expert panel, seven underwent review, with only three candidates meeting the following consensus criteria of relevant mechanisms for targeting neurodegenerative pathways, non-clinical efficacy, and tolerability in older individuals. The three agents were: [1] the live attenuated herpes zoster (HZ) vaccine (Zostavax) [2], sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, and [3] riluzole, a glutamate antagonist. The HZ vaccine additionally offers potential for population-level dementia risk reduction.

CONCLUSION: This Delphi consensus identified three high-priority drug repurposing candidates for AD with favourable safety profiles and mechanistic plausibility, which are considered suitable for pragmatic clinical trials, including remote or hybrid designs. The PROTECT platform, which supports international cohorts in the UK, Norway, and Canada, offers a well-established means to conduct such trials effectively, thus helping to accelerate the evaluation and potential deployment of these drug candidates to benefit individuals with or at risk for AD.},
}

*Drug Repositioning/methods
*Alzheimer Disease/drug therapy
Humans
Delphi Technique
Consensus
Stakeholder Participation

@article {pmid41249122,
year = {2025},
author = {Diamandis, N and van den Anker, JN and Denisova, K},
title = {Effect of Alzheimer's disease medications on neurocognitive outcomes in children and adolescents with autism spectrum disorder and low IQ: a scoping review.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {475},
pmid = {41249122},
issn = {2158-3188},
support = {R01MH121605//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 614242//Simons Foundation/ ; },
mesh = {Humans ; Child ; Adolescent ; *Autism Spectrum Disorder/drug therapy/complications/psychology ; *Alzheimer Disease/drug therapy/complications ; *Intellectual Disability/complications ; Young Adult ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Child, Preschool ; },
abstract = {BACKGROUND: Individuals with autism spectrum disorder (ASD) and comorbid intellectual disability (ID) are particularly vulnerable to poor developmental trajectories. These individuals are at increased risk of Alzheimer's disease (AD) relative to those without comorbid ID and the general population. Considering that there could be an important mechanistic link underlying ASD and AD, individuals with these conditions may stand to benefit from similar psychopharmacological treatments.

METHODS: This scoping review aimed to evaluate and synthesize the evidence on the effect of AD medications on neurocognitive outcomes in children and adolescents with ASD and low intelligence quotient (IQ). We performed the search according to PRISMA guidelines from inception to May 21[st], 2025 in four databases: PubMed, PsycInfo, Scopus, and Web of Science. We included studies of children and adolescents (2 - 21 years) with ASD and low IQ (<85) treated with at least one Food and Drug Administration (FDA)-approved AD medication (donepezil, galantamine, rivastigmine, benzgalantamine, memantine, aducanumab, lecanemab or donanemab) and investigating neurocognitive outcomes.

RESULTS: Twelve studies met the eligibility criteria. Six studies reported on neurocognitive outcomes from N-methyl-D-aspartate (NMDA) receptor antagonist treatment and six studies from cholinesterase inhibitor treatment. Among studies reporting on cholinesterase inhibitors, significant improvement was detected in language (60% of five reporting studies), executive function (100% of two reporting studies), complex attention (100% of one reporting study), and general cognitive ability (50% of two reporting studies). Among the NMDA receptor antagonist studies, evidence of improvement was detected in language (60% of five reporting studies), executive function (75% of four reporting studies), learning and memory (100% of two reporting studies), perceptual-motor functioning (66.6% of three reporting studies), complex attention (100% of one reporting study), and general cognitive ability (50% of two reporting studies). Across studies, treatment with either a cholinesterase inhibitor or an NMDA receptor antagonist was associated with improvements in language, executive function, complex attention, and general cognitive ability. A pattern of significance was detected with age, in that younger children may benefit more from these medications than adolescents.

CONCLUSION: This scoping review identified promising evidence of neurocognitive improvement in children and adolescents with ASD and low IQ following treatment with either a cholinesterase inhibitor or an NMDA receptor antagonist. Considering the lack of FDA-approved treatments for the cognitive deficits associated with ASD and an absence of medications approved to treat core features of ASD, our findings highlight an opportunity for innovative directions in autism research and treatment.},
}

Humans
Child
Adolescent
*Autism Spectrum Disorder/drug therapy/complications/psychology
*Alzheimer Disease/drug therapy/complications
*Intellectual Disability/complications
Young Adult
*Cholinesterase Inhibitors/therapeutic use/pharmacology
Child, Preschool

@article {pmid41249052,
year = {2025},
author = {Szatmari, EM and Moran, C and Cohen, SJ and Bashtovyy, D and Jacob, A and Bunner, W and Phipps, M and Lora, JC and Stackman, RW and Yasuda, R},
title = {Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer's Disease.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0063-25.2025},
pmid = {41249052},
issn = {2373-2822},
abstract = {ArfGAP, with dual PH domain-containing protein 1/Centaurin-α1 (ADAP1/CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics. CentA1 upregulation and association with amyloid plaques in the human Alzheimer's disease (AD) brain suggest a role for this protein in AD progression. To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 KO mice with the J20 mouse model of AD. We evaluated AD-associated behavioral and neuropathological hallmarks and gene expression profiles in J20 and J20 crossed with CentA1 KO (J20xKO) male mice to determine the impact of eliminating CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris Water Maze test showed significant impairment in J20 mice, which was rescued in J20xKO mice. Moreover, neuropathological hallmarks of AD, such as amyloid plaque deposits and neuroinflammation, were significantly reduced in J20xKO mice. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes (DEGs) between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20xKO vs J20) were anti-correlated with changes caused by APP overexpression (J20 vs WT), consistent with rescue of J20 phenotypes by CentA1 KO. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes in this model and that targeting CentA1 signaling might have therapeutic potential for AD prevention or treatment.Significance statement ADAP1/Centaurin-α1 (CentA1) is highly enriched in the brain, and increased CentA1 level has been linked to Alzheimer's disease (AD). However, the precise role of CentA1 in the pathogenesis of AD is poorly understood. We found that genetic deletion of CentA1 in the AD model mice rescues the pathological hallmarks of AD, including loss of dendritic spines in the hippocampus, amyloid plaque deposition, neuroinflammation, and spatial memory deficits. Transcriptome analysis of the forebrain demonstrated that gene expression changes caused by APP overexpression were restored in J20 mice lacking CentA1. These findings support the role of CentA1 in AD progression.},
}